5, 6-bisaryl-2-pyridine-carboxamide derivatives, preparation and application thereof in therapeutics as urotensin II receptor antagonists

ABSTRACT

The present invention relates to derivatives of 5,6-bisaryl-2-pyridine-carboxamide, their preparation and their application in therapeutics as antagonists of urotensin II receptors.

This application is a divisional of U.S. patent application Ser. No. 12/369,200 filed Feb. 11, 2009, which is a continuation of International Patent Application No. PCT/FR2007/001357, filed Aug. 9, 2007, which claims priority to French Patent Application FR 0607283, filed Aug. 11, 2006, the contents of all of which are incorporated herein by reference.

The present invention relates to derivatives of 5,6-bisaryl-2-pyridine-carboxamide, their preparation and their application in therapeutics as antagonists of urotensin II receptors.

Urotensin II is a cyclic peptide comprising 11 amino acids and is considered to be one of the most powerful vasoconstrictors known to date (Ames et al., 1999, Nature 401, 282-286). Its biological activity is mediated by the activation of a receptor with 7 transmembrane domains coupled to proteins G, called GPR14, renamed UT (Urotensin II Receptor) by the International Union of Basic and Clinical Pharmacology (IUPHAR). Activation of urotensin II receptor leads to mobilization of intracellular calcium. Urotensin II and its receptor are strongly expressed in the cardiovascular system, as well as at the renal and cerebral level and in the endocrine system (Richards and Charles, 2004, Peptides 25, 1795-1802). On isolated vessels, human urotensin II causes vasoconstriction, the intensity of which varies in relation to the particular region and species (Douglas et al., 2000, Br. J. Phamacol. 131, 1262-1274). The administration of urotensin II in an anaesthetized primate induces an increase in peripheral vascular resistances and a deterioration of contractility and of cardiac output, which at high doses may lead to cardiovascular collapse and ultimately to the death of the animal (Ames et al., 1999, Nature 401, 282-286). Moreover, urotensin II stimulates the proliferation of the vascular smooth muscle cells and acts in synergy with the mitogenic activity of serotonin and of oxidized LDLs (Low Density Lipoproteins) (Watanabe et al., 2001, Circulation 104; 16-18). On cardiomyocytes in culture, urotensin II induces cellular hypertrophy and an increase in the synthesis of extracellular matrix (Tzanidis A. et al., 2003, Circ. Res. 93, 246-253).

The plasma and urinary levels of urotensin II have been reported to be increased in a certain number of cardiovascular, renal and metabolic pathologies in humans. These pathologies include arterial hypertension, heart failure, renal failure, diabetes and hepatic cirrhosis (Richards and Charles, 2004, Peptides 25, 1795-1802; Doggrell, 2004, Expert Opin Investig Drugs 13, 479-487).

Central effects of urotensin II have also been described (Matsumoto Y. et al., Neurosci. Lett., 2004, 358, 99).

Finally, it has been shown that some tumour cell lines overexpress the urotensin II receptor (Takahashi K. et al., Peptides, 2003, 24, 301).

Antagonists of the urotensin II receptors may be useful for the treatment of congestive heart failure, ischaemic heart disease, myocardial infarction, cardiac hypertrophy and fibrosis, coronary diseases and atherosclerosis, systemic and pulmonary arterial hypertension, post-angioplasty restenosis, acute and chronic renal failure of diabetic and/or hypertensive origin, diabetes, vascular inflammation, and aneurysms. Furthermore, antagonists of the urotensin II receptors may be useful for the treatment of disorders of the central nervous system, including neurodegenerative diseases, cerebrovascular accidents, stress, anxiety, aggressiveness, depression and schizophrenia, as well as vomiting and sleep disorders.

Finally, antagonists of the urotensin II receptors may also be useful for the treatment of some cancers.

The compounds according to the present invention correspond to formula (I):

in which:

X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen or halogen atom or an alkyl or alkoxy group;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group;

A represents an aryl, heteroaryl or heterocycloalkyl group;

W represents a halogen atom, an alkyl group or a haloalkyl group;

Z represents a bond, a cycloalkylene group or an alkylene group optionally substituted with one or more groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently         of one another, an alkyl, cycloalkyl, hydroxyalkyl or         fluoroalkyl group, or alternatively R4 and R5 form, with the         nitrogen atom to which they are attached, a 5- or 6-membered         ring, such as a pyrrolidinyl or piperidinyl ring, optionally         substituted with an alkyl group,     -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an         alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these         groups being optionally substituted with one or more groups         selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,         hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being         different from a hydrogen atom,     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a mono- or polycyclic system selected from:         cycloalkyl, indanyl, tetrahydropyranyl, piperidine,         tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl         and adamantyl, said mono- or polycyclic system being optionally         substituted, in any position (including on a nitrogen atom, if         applicable) with one or more groups selected from a halogen atom         and the alkyl, fluoroalkyl, hydroxy, alkoxy, —O—CO-alkyl and         acyl groups;

p represents an integer equal to 0 or 1.

The compounds of formula (I) can have one or more asymmetric carbon atoms. They can therefore be in the form of enantiomers or of diastereoisomers. These enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) can be in the state of bases or can be salified by acids or bases, notably pharmaceutically acceptable acids or bases. Said salts of addition form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that can be used, for example, for the purification or isolation of the compounds of formula (I), also form part of the invention.

The compounds of formula (I) can also be in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Said hydrates and solvates also form part of the invention.

Among the compounds of formula (I), we may mention the compounds of formula (I′):

in which:

X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen or halogen atom or an alkyl or alkoxy group;

A represents an aryl, heteroaryl or heterocycloalkyl group selected from the phenyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and pyrrolidinone groups, said aryl, heteroaryl or heterocycloalkyl group being optionally substituted in any positions with 1 to 3 groups selected from a halogen atom and the alkyl, fluoroalkyl, hydroxy, alkoxy, —NRR′, —NR—CO-alkyl, —SO— and —SO₂-alkyl groups, where R and R′ represent, independently of one another, a hydrogen atom or an alkyl group;

W represents a halogen atom, an alkyl group or a fluoroalkyl group;

Z represents a bond, a cycloalkylene group or an alkylene group optionally substituted with 1 or 2 groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups;

B represents:

either a group —NR4R5, where R4 and R5 represent, independently of one another, an alkyl, cycloalkyl or fluoroalkyl group, or alternatively R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionally substituted with an alkyl group,

or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an         alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these         groups being optionally substituted with one or more groups         selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,         hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being         different from a hydrogen atom,     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a mono- or polycyclic system selected from:         cycloalkyl, indanyl, tetrahydropyranyl, piperidine,         tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl         and adamantyl, said mono- or polycyclic system being optionally         substituted, in any position with one or more groups selected         from a halogen atom and the alkyl, fluoroalkyl, hydroxy, alkoxy,         formyl and acetyl groups;

p represents 0 or 1.

Among the compounds of formula (I) according to the invention, we may mention a subgroup of compounds which is defined as follows:

X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen atom or an alkoxy group;

and/or

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group;

and/or

A represents an aryl, heteroaryl or heterocycloalkyl group selected from the phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl and pyrrolidinone groups, said aryl or heteroaryl group being optionally substituted in any positions with one or more groups selected from a halogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkyl groups, where R and R′ represent, independently of one another, a hydrogen atom or an alkyl group and p is an integer between 1 and 5 and more particularly between 1 and 3;

and/or

W represents a halogen atom, an alkyl group or a haloalkyl group;

and/or

Z represents a bond or an alkylene group optionally substituted with at least one group selected from a halogen atom and the alkyl and hydroxy groups;

and/or

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently         of one another, an alkyl, hydroxyalkyl group, or alternatively         R4 and R5 form, with the nitrogen atom to which they are         attached, a 5- or 6-membered ring, such as a pyrrolidinyl or         piperidinyl ring,     -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group;

and/or

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an         alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these         groups being optionally substituted with one or more hydroxy         groups, at least one of R1 or R2 being different from a hydrogen         atom,     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a mono- or polycyclic system selected from:         cycloalkyl, indanyl, tetrahydropyranyl, piperidine,         bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said         mono- or polycyclic system being optionally substituted, in any         position (including on a nitrogen atom, if applicable) with one         or more groups selected from the alkyl, hydroxy, acetyl and         alkoxy groups;

and/or

p represents an integer equal to 0 or 1.

Among the compounds of formula (I) according to the invention, we may mention a second subgroup of compounds for which X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen or halogen atom or an alkyl or alkoxy group.

More particularly, among the compounds of formula (I) of the second subgroup according to the invention, we may mention a subgroup of compounds for which X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen atom or an alkoxy group.

Among the compounds of formula (I) according to the invention, we may mention a third subgroup of compounds for which U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group.

Among the compounds of formula (I) according to the invention, we may mention a fourth subgroup of compounds for which A represents an aryl, heteroaryl or heterocycloalkyl group optionally substituted.

More particularly, among the compounds of formula (I) of the fourth subgroup according to the invention, we may mention a subgroup of compounds for which A represents an aryl, heteroaryl or heterocycloalkyl group selected from the phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and pyrrolidinone groups, said aryl, heteroaryl or heterocycloalkyl group being optionally substituted in any positions with one or more groups selected from a halogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl, —SO— and —SO₂-alkyl groups, where R and R′ represent, independently of one another, a hydrogen atom or an alkyl group and p is an integer between 1 and 5.

Even more particularly, among the compounds of formula (I) of the fourth subgroup according to the invention, we may mention a subgroup of compounds for which A represents a group selected from the phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl and pyrrolidinone groups, said aryl or heteroaryl group being optionally substituted in any positions with one to three groups selected from a halogen atom and the cyano, alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkyl groups, where R and R′ represent, independently of one another, a hydrogen atom or an alkyl group and p is an integer between 1 and 3.

Among the compounds of formula (I) according to the invention, we may mention a fifth subgroup of compounds for which W represents a halogen atom, an alkyl group or a haloalkyl group.

Among the compounds of formula (I) according to the invention, we may mention a sixth subgroup of compounds for which Z represents a bond, a cycloalkylene group or an alkylene group optionally substituted with 1 or 2 groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups.

More particularly, among the compounds of formula (I) of the sixth subgroup according to the invention, we may mention a subgroup of compounds for which Z represents a bond or an alkylene group optionally substituted with at least one group selected from a halogen atom and the alkyl and hydroxy groups.

Among the compounds of formula (I) according to the invention, we may mention a seventh subgroup of compounds for which B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently         of one another, an alkyl, cycloalkyl, hydroxyalkyl or         fluoroalkyl group, or alternatively R4 and R5 form, with the         nitrogen atom to which they are attached, a 5- or 6-membered         ring, such as a pyrrolidinyl or piperidinyl ring, optionally         substituted with an alkyl group,     -   or a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group.

More particularly, among the compounds of formula (I) of the seventh subgroup according to the invention, we may mention a subgroup of compounds for which B represents a group —NR4R5, where R4 and R5 represent, independently of one another, an alkyl, cycloalkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionally substituted with an alkyl group.

Even more particularly, among the compounds of formula (I) of the seventh subgroup according to the invention, we may mention a subgroup of compounds for which B represents a group —NR4R5, where R4 and R5 represent, independently of one another, an alkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring.

More particularly, among the compounds of formula (I) of the seventh subgroup according to the invention, we may mention a subgroup of compounds for which B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group.

Among the compounds of formula (I) according to the invention, we may mention an eighth subgroup of compounds for which R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an         alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these         groups being optionally substituted with one or more groups         selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy,         hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being         different from a hydrogen atom,     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a mono- or polycyclic system selected from:         cycloalkyl, indanyl, tetrahydropyranyl, piperidine,         tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl         and adamantyl, said mono- or polycyclic system being optionally         substituted, in any position (including on a nitrogen atom, if         applicable) with one or more groups selected from a halogen atom         and the alkyl, fluoroalkyl, hydroxy, alkoxy, —O—CO-alkyl and         acyl groups.

More particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these groups being optionally substituted with one or more groups selected from halogen atoms and the alkyl, fluoroalkyl, alkoxy, hydroxy and —O—CO-alkyl groups, at least one of R1 or R2 being different from a hydrogen atom.

Even more particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, phenyl, benzyl or —CH₂-indolyl group, these groups being optionally substituted with one or more hydroxy groups, at least one of R1 or R2 being different from a hydrogen atom.

More particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 together form, with the carbon atom to which they are attached, a mono- or polycyclic system selected from: cycloalkyl, indanyl, tetrahydropyranyl, piperidine, tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- or polycyclic system being optionally substituted, in any position (including on a nitrogen atom, if applicable) with one or more groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 together form, with the carbon atom to which they are attached, a mono- or polycyclic system selected from: cycloalkyl, indanyl, tetrahydropyranyl, piperidine, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- or polycyclic system being optionally substituted, in any position (including on a nitrogen atom, if applicable) with one or more groups selected from the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 together form, with the carbon atom to which they are attached, a mono- or polycyclic system selected from: cycloalkyl, indanyl, tetrahydropyranyl, piperidine, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- or polycyclic system being optionally substituted, on a carbon atom, with one or more groups selected from the alkyl, hydroxy and alkoxy groups.

Even more particularly, among the compounds of formula (I) of the eighth subgroup according to the invention, we may mention a subgroup of compounds for which R1 and R2 together form, with the carbon atom to which they are attached, a mono- or polycyclic system selected from: cycloalkyl, indanyl, tetrahydropyranyl, piperidine, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and adamantyl, said mono- or polycyclic system being optionally substituted, on a nitrogen atom, with a group selected from the alkyl and acyl groups.

Among the compounds of formula (I) according to the invention, we may mention a ninth subgroup of compounds for which p represents an integer equal to 0 or 1.

Within the scope of the present invention, and unless stated otherwise in the text, the following definitions are used:

-   -   halogen atom: a fluorine, chlorine, bromine or iodine atom;     -   alkyl group: a saturated linear aliphatic group, comprising 1 to         5 carbon atoms or when the alkyl chain has at least three carbon         atoms it can be linear, branched or partially cyclized. As         examples, we may mention the methyl, ethyl, propyl, isopropyl,         butyl, isobutyl, tertbutyl, pentyl, methylene-cyclopropyl         groups;     -   alkylene group: an alkyl group as defined above, which is         divalent. As examples, we may mention a dimethylene (—CH₂—CH₂—),         propylene, butylene, ethylene, or 2-methylpropylene group;     -   cycloalkyl group: a saturated cyclic group, which has from 3 to         8 carbon atoms and which is cyclic. As examples, we may mention         the cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups;     -   heterocycloalkyl group: a cycloalkyl group as defined above, in         which one or two carbons have been substituted with a nitrogen         atom. As examples, we may mention the pyrrolidinone group and         the piperidine group;     -   aryl group: a monocyclic aromatic group comprising 5 or 6 carbon         atoms, for example a phenyl group;     -   heteroaryl group: a cyclic aromatic group comprising 5 or 6         atoms, one or more of which are heteroatoms such as N and/or S.         As examples of heteroaryl groups, we may mention a thienyl,         thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,         pyrazolyl group;     -   cycloalkylene group: a cycloalkyl group as defined above which         is divalent;     -   fluoroalkyl group: an alkyl group as defined above, in which one         or more hydrogen atoms have been substituted with a fluorine         atom. As an example, we may mention the trifluoromethyl group;     -   alkoxy group: a group of formula —O-alkyl where the alkyl group         is as defined previously.

Among the compounds described in the present invention, we may mention a subgroup of compounds corresponding to formula (I) in which:

X and Y represent, independently of one another, a nitrogen atom or a CH group;

A represents a phenyl, pyridinyl, or pyrrolidinone group, substituted in any positions with 1 to 2 groups selected from a halogen atom, such as chlorine or fluorine, and the alkyl, trifluoromethyl, methoxy and N,N-dimethylamine groups;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom;

W represents a chlorine atom or a trifluoromethyl group;

Z represents a bond or an alkylene group optionally substituted with a methyl group;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently         of one another, an alkyl group or alternatively R4 and R5 form,         with the nitrogen atom to which they are attached, a 5- or         6-membered ring,     -   or heterocycles of the following formula:

where m=1 or 2 and R6 represents an ethyl or methyl group;

R1 and R2 represent:

-   -   either, independently of one another, a hydrogen atom or an         isopropyl, tertbutyl group;     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a mono- or polycyclic system selected from:         cycloalkyl (such as cyclopentyl, cyclohexyl, or cycloheptyl),         tetrahydropyranyl, bicyclo[2.2.1]heptyl, bicyclo[3.3.1]nonyl and         adamantyl, said cycloalkyl group being optionally substituted in         positions 3 and 4 with a methyl, hydroxy or methoxy group or one         or two halogen atoms such as fluorine;

p represents 0 or 1.

We may also mention a second subgroup of compounds among the preferred compounds corresponding to formula (I) in which:

X represents a nitrogen atom and Y represents a CH group;

A represents a phenyl or pyridinyl group, substituted in positions 2, 4, 5 and 6 by one or two groups selected from a halogen atom, such as chlorine or fluorine, and the alkyl groups, such as methyl, ethyl or isopropyl, trifluoromethyl, methoxy and N,N-dimethylamine;

U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom;

W represents a chlorine atom or a trifluoromethyl group;

Z represents a bond or an ethylene, propylene or methylpropylene group;

B represents:

-   -   either a group —NR4R5, where R4 and R5 represent, independently         of one another, a methyl, ethyl or propyl group or form together         with the nitrogen atom to which they are attached a 5- or         6-membered ring,     -   or a heterocycle of the following formula:

R1 and R2 represent:

-   -   either R1 is a hydrogen atom and R2 an isopropyl, tertbutyl         group, the carbon atom bearing groups R1 and R2 adopting the         absolute configuration S,     -   or R1 and R2 together form, with the carbon atom to which they         are attached, a cycloalkyl group (such as cyclohexyl or         cycloheptyl), and adamantyl, said cycloalkyl group being         optionally substituted in positions 3 and 4 with a methyl,         hydroxy or methoxy group,

p represents 0 or 1.

Among the compounds according to the invention, we may notably mention the following compounds:

-   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4-methoxy-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-difluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethoxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-fluoro-6-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(2-methoxyethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methoxymethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(5-[2-chloro-5-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethyl-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-4-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-ethoxy-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)-2-fluoropropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)-5-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(2-methoxyethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(methoxymethyl)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(1-methylethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methyl-5-(2-methylpropoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[5-(cyclopropylmethoxy)-2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methyl-5-propoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-2,3-dihydro-1H-indene-2-carboxylic     acid -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclopentanecarboxylic     acid -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[2.2.1]heptane-2-carboxylic     acid hydrochloride -   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}phenylalanine -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic     acid -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-phenylbutanoic     acid -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-4-(1H-indol-3-yl)butanoic     acid -   ({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)(phenyl)acetic     acid -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclohexylpropanoic     acid -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid -   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-alpha-methylphenylalanine -   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}-3-methylisovaline -   2-({[6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[(1-ethylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-phenylpyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3.4′-bipyridin-6-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic     acid -   3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic     acid hydrochloride -   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}-3-hydroxyphenylalanine     hydrochloride -   2-({[6-{4-chloro-3-[2-(1-methylpyrrolidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[2-(1-methylpiperidin-2-yl)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(trifluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   2-({[6-(4-chloro-3-{3-[cyclopropyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(dimethylamino)phenyl]pyridin-2-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)tetrahydro-2H-pyran-4-carboxylic     acid hydrochloride -   (3R)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic     acid hydrochloride -   2-[({6-[4-chloro-3-(3-piperidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-[({6-[4-chloro-3-(2-piperidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic     acid hydrochloride -   2-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic     acid hydrochloride -   2-[({6-[4-chloro-3-(3-pyrrolidin-1-ylpropoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]adamantane-2-carboxylic     acid hydrochloride -   2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylcyclohexanecarboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[3-(dimethylamino)-1-methylpropoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   2-({[6-(4-chloro-3-{[(2R)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   2-({[6-(4-chloro-3-{[(2S)-3-(dimethylamino)-2-hydroxypropyl]oxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   acetyl-4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)piperidine-4-carboxylic     acid hydrochloride -   2-({[6-{4-chloro-3-[2-(diethylamino)ethoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   [1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexyl]acetic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[3-amino-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic     acid hydrochloride -   cis-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylic     acid hydrochloride -   trans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4-methoxycyclohexanecarboxylic     acid hydrochloride -   trans-1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(methylsulphonyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-methyl-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(5-[2-(acetylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   N-{[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}-D-valine     hydrochloride -   1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(2-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-4′-methyl-3.3′-bipyridin-6-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-[({6-[4-chloro-3-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylphenyl)pyridin-2-yl}carbonyl)amino]-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[4-(dimethylamino)butoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(1-methylethyl)phenyl]pyridin-2-yl)carbonyl]amino}-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-chloro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-(4-chloro-3-{3-[methyl(propyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)-2-methylpropoxy]phenyl}-5-(2-ethylphenyl)pyridin-2-yl]carbonyl}amino)-3-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-propylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-fluoro-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexanecarboxylic     acid hydrochloride -   1-({[3-chloro-2′-(4-chloro-3-{3-[ethyl(methyl)amino]propoxy}phenyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cycloheptanecarboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{3-[3-(dimethylamino)propoxy]-4-ethylphenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclobutylpropanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylthiophen-3-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-3-cyclopropylpropanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-hydroxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4,5-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-methyl-1,3-thiazol-4-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   4-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)oxepane-4-carboxylic     acid hydrochloride -   3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-cyanophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-fluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-6-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-(4-chloro-3-{3-[(2-hydroxyethyl)(methyl)amino]propoxy}phenyl)-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3-hydroxy-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(4,5-difluoro-2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(6-methyl-1,3-benzodioxol-5-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-diethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[5-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(difluoromethyl)-2,3′-bipyridin-6′-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-methylphenyl]-3-[methylamino]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(5-ethyl-3-methyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(5-[2-chloro-4-(dimethylamino)phenyl]-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-chloro-5-(trifluoromethoxy)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride -   1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dichlorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-difluorocyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-3-(methylamino)-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-fluorophenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-4-methoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic     acid hydrochloride -   1-{[(6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-[2-(difluoromethyl)phenyl]pyridin-2-yl)carbonyl]amino}cyclohexanecarboxylic     acid hydrochloride

In accordance with the invention, the compounds of general formula (I) can be prepared according to the method given below, shown in scheme 1.

When, in the starting compound of formula (XI), X represents a nitrogen atom, Y represents a carbon atom (i.e. a group of formula —CR₃— as defined with reference to the compounds of formula (I) according to the invention) and U represents a hydrogen atom, or alternatively X represents a carbon atom, Y represents a nitrogen atom and U represents a hydrogen atom, or alternatively X and Y represent a nitrogen atom and U represents a hydrogen atom, then we can carry out, in a stage (i), a coupling reaction of the SUZUKI type, catalysed by a palladium (0) derivative such as tetrakis(triphenylphosphine)palladium (0) [Pd(PPh₃)₄], between the compound of formula (XI) (where Q=OH or Br and T=halogen atom, such as a bromine or iodine atom) and a boronic acid of formula (IX), where GP represents a benzyl group optionally substituted with one or more alkoxy groups, in the presence of a base such as potassium phosphate and in a solvent such as N,N-dimethylformamide (DMF) at a temperature of about 95° C. This reaction permits regioselective substitution of function T with the phenoxy nucleus to give compound (VIII).

The OH function of compound (VIII) is then converted to a leaving group such as trifluoromethanesulphonate (OTf), in stage (ii), by means of trifluoromethanesulphonic anhydride in the presence of a base such as triethylamine (TEA) and in a solvent such as dichloromethane (DCM) to give the compound of formula (VII).

The trifluoromethanesulphonate group thus obtained makes it possible, owing to its reactivity, to introduce, in stage (iii), the nucleus A by an organopalladium coupling reaction of the type:

-   -   either SUZUKI, between compound (VII) and a boronic acid or         ester of respective formulae A-B(OH)₂ or

in the presence of a catalytic amount of a palladium derivative such as Pd(PPh₃)₄, in the presence of a base such as potassium phosphate and of a solvent such as DMF, at a temperature of 90° C.;

-   -   or STILLE, between compound (VII) and an aryltributylstannane or         heteroarylstannane derivative ASnBu₃ in the presence of a         catalytic amount of copper iodide (CuI) and of a derivative of         palladium (II) such as         [1,1′-bis(cyclopentadienyldiphenylphosphino)ferrocene]palladium (II)         dichloride [PdCl₂(dppf)] and of a solvent such as 1,4-dioxan at         a temperature of 90° C.;     -   or HARTWIG-BUCHWALD, between compound (VII) and an amide such as         2-pyrrolidinone, in the presence of a catalytic amount of a         phosphine such as         9,9-dimethyl-4,5-bis-(diphenylphosphino)xanthene (XantPhos) and         of a derivative of palladium (0) such as         tris(dibenzylideneacetone)dipalladium (0) [Pd₂(dba)₃], using a         base such as caesium carbonate, and in a solvent such as DMF at         a temperature of 70° C.

We thus obtain compound (VI).

Alternatively, in the starting compound of formula (XI), when X and Y represent carbon atoms and U represents a hydrogen atom, Q an iodine atom and T a bromine atom, or alternatively X and Y represent a nitrogen atom and U represents a group NHR (as defined with reference to the compounds of formula (I) according to the invention), Q and T atoms of chlorine, bromine or iodine, the order of introduction of groups A and phenoxy on the starting phenyl nucleus is reversed (scheme 1).

In this case, a first reaction of the SUZUKI type (stage (iv)) with a boronic acid A-B(OH)₂ permits the selective introduction of a group A in place of the halogen atom Q. The reaction is carried out in the presence of a catalytic amount of a palladium derivative such as Pd(PPh₃)₄ and of a base such as caesium carbonate, in a solvent such as DMF at a temperature of 90° C. Then a second reaction of the SUZUKI type is carried out (stage (v)) between the boronic ester (XII) or the boronic acid (IX) and compound (X), in the presence of a catalytic amount of a palladium derivative such as Pd(PPh₃)₄ and of a base such as caesium carbonate, in a solvent such as DMF at a temperature of 90° C. We thus obtain compound (VI).

Deprotection of the phenol function of the compound of formula (VI) by boron tribromide at −78° C., trifluoroacetic acid (TFA) at room temperature or hydrogen chloride at 0° C. in DCM (stage (vi)) leads to the compound of formula (V).

The introduction of group Z—B in stage (vii) can be carried out:

-   -   either by alkylation of compound (V) with a chlorine derivative         Cl—Z—B in the presence of a weak inorganic base such as caesium         carbonate and in a polar aprotic solvent such as DMF at a         temperature between 80 and 100° C., such as 90° C.,     -   or by MITSUNOBU reaction between compound (V) and an alcohol of         formula HO—Z—B in the presence of triphenylphosphine,         diisopropyl azodicarboxylate (DIAD), and a catalytic amount of a         weak organic base such as TEA at 0° C. in an aprotic solvent         such as tetrahydrofuran (THF).

The compound of formula (IV) is then saponified in stage (viii), by means of a strong inorganic base such as potassium hydroxide in a water/methanol mixture maintained at room temperature (RT) or heated under reflux, to give, after acidification with a strong acid such as 1N hydrochloric acid (HCl), compound (III).

Within the scope of the present invention, room temperature means a temperature between 20 and 25° C.

A peptide coupling reaction (stage (ix)) between compound (III) and amines of formula (II) in the presence of a coupling agent such as carbonyldiimidazole (CDI), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium tetrafluoroborate (TBTU) or N-[3-(dimethylamino)propyl-N′-ethyl carbodiimide hydrochloride (EDC.HCl) and of an organic base such as N,N′-diisopropylethylamine (DIEA) and in a polar aprotic solvent such as DMF at room temperature leads to the compounds of formula (I) according to the present invention.

Scheme 2 describes the synthesis of the boronic derivatives (IX) and (XII).

The Case when W═CF₃

2-Amino-5-nitrophenol (XVI) is converted to the iodine derivative (XV) by a SANDMEYER reaction in an aqueous environment at 0° C., in the presence of sodium iodide and with a co-solvent such as dimethylsulphoxide (DMSO). Protection of the phenol function (stage i) by a benzyl group is effected with a halogen derivative such as benzyl bromide in the presence of a base such as potassium carbonate (K₂CO₃) in a solvent such as DMF at 60° C. Substitution of the iodine atom with the trifluoromethyl group (Eur. J. Org. Chem. (2003) pp. 1559-1568), carried out with trifluoromethyltrimethylsilane in the presence of CuI and potassium fluoride in a solvent such as N-methylpyrrolidinone (NMP) at 45° C. (stage ii), leads to compound (XIV) which, after reduction of the nitro function to an amino function by a reducing agent such as iron at 70° C. in an ethanol (EtOH)/water/acetic acid (AcOH) mixture, is converted to the iodine derivative (XIII) by means of a second SANDMEYER reaction (stage iii).

In stage (iv), a reaction of metal-halogen exchange effected between compound (XIII) and isopropyl magnesium chloride (iPrMgCl) at −50° C. in a solvent such as THF, followed by addition of triisopropylborate, leads after acidolysis with an acid such as HCl 5N, to boronic acid (IX).

The Case when W═Cl

Protection of the 2-chloro-5-iodophenol (XVIIa) by a benzyl or para-methoxybenzyl group as described in stage (i) leads to the iodine derivative (XVII) which can be converted:

-   -   either, in stage (iv), to boronic acid (IX) as described         previously,     -   or, in stage (v), to boronic ester (XII) by a coupling reaction         with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-dioxaborolane in the         presence of a base such as potassium acetate (KOAc) and a         catalytic amount of a palladium derivative (II) such as         [PdCl₂(dppf)], in a solvent such as DMSO at 100° C.

Alternatively, a subgroup of compounds of formula (Ia) according to the present invention, where group A represents a 2,6-dimethoxybenzene nucleus, was prepared in the following way (scheme 3):

-   -   Condensation of 2,6-dimethoxybenzaldehyde on 2-cyanoacetic acid         (stage i) in the presence of ammonium acetate and a base such as         pyridine, heating under reflux of a solvent such as toluene,         leads to derivative (XX).     -   Derivative (XX) is then treated with diisobutylaluminium hydride         (DIBAL-H) at 0° C. in a solvent such as toluene. The aldehyde         thus obtained is reacted (stage ii) with ethyl 2-azido acetate         at −10° C. in the presence of a base such as sodium ethoxide in         a solvent such as ethanol to obtain the diene (XIX). In stage         (iii), treatment of diene (XIX) with triphenylphosphine at RT in         a solvent such as DCM leads to azatriphenylphosphoranylidene         (XVIII).     -   Reaction (stage iv) between derivative (XVIII) and the         aldehyde (XVII) in a solvent such as acetonitrile leads, via the         cyclization in situ at 100° C. of an intermediate imine         according to an electrocyclic cyclization/dehydrogenation         multistep process, to the pyridine derivative (IVa).     -   The steps of alkylation or MITSUNOBU reaction (stage v),         saponification (stage vi) then peptide coupling (stage vii)         described previously in scheme 1 and applied to derivative (IVa)         lead to the compounds of formula (Ia) according to the present         invention.

In schemes 1 and 2, when the method of preparation of the starting compounds, the intermediates and the reagents is not described, they are available commercially or are described in the literature, or alternatively can be prepared according to methods that are known by a person skilled in the art.

The following examples illustrate the preparation of some compounds according to the invention. The numbering of the compounds in the examples refers to the table given later showing the chemical structures and physical properties of some compounds according to the invention.

The following abbreviations are used:

-   EtOAc Ethyl acetate -   AcOH Acetic acid -   BSA N,O-Bis(trimethylsilyl)acetamide -   CDI Carbonyldiimidazole -   CuI Copper iodide -   DCM Dichloromethane -   DIBAL-H Diisobutylaluminium hydride -   DIAD Diisopropyl azodicarboxylate -   DME Dimethoxyethane -   DMF Dimethylformamide -   DMSO Dimethyl sulphoxide -   EDC.HCl N-[3-(Dimethylamino)propyl-N′-ethyl carbodiimide     hydrochloride -   EtOH Ethanol -   h Hour(s) -   HCl Hydrochloric acid -   K₂CO₃ Potassium carbonate -   KOAc Potassium acetate -   K₃PO₄ Potassium phosphate or tripotassium tetraoxophosphate -   Na₂CO₃ Sodium carbonate -   NH₄Cl Ammonium chloride -   NaHCO₃ Sodium bicarbonate -   Na₂SO₄ Sodium sulphate -   NMP N-methylpyrrolidinone -   PdCl₂ (dppf)     [1,1′-bis(Cyclopentadienyldiphenylphosphino)ferrocene]palladium (II)     dichloride -   Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium (0) -   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium (0) -   TBTU     N-[(1H-Benzotriazol-1-yloxy)(dimethylamino)methylidene]-N-methylmethanaminium     tetrafluoroborate -   TEA Triethylamine -   TFA Trifluoroacetic acid -   THF Tetrahydrofuran -   RT Room temperature

EXAMPLE 1 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid Compound No. 12 1.1. (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile

Add, one after another, 1.13 g (14.7 mmol) of ammonium acetate, 40.4 mL (500 mmol) of pyridine and 31.2 g (367 mmol) of 2-cyanoacetic acid to a solution of 61 g (367 mmol) of 2,6-dimethoxybenzaldehyde in 360 mL of toluene. Reflux the reaction mixture for 15 h, distilling the toluene-water azeotrope in Dean-Stark apparatus. Take up the solution in 500 mL toluene and 40 mL pyridine and reflux again for 48 h in the Dean-Stark apparatus. After concentration under reduced pressure, take up the residue in 800 mL of dichloromethane (DCM) and wash successively with 1 L of 1N HCl aqueous solution, 500 mL of saturated aqueous solution of sodium carbonate (Na₂CO₃) and 1 L of water. After drying over sodium sulphate (Na₂SO₄) and concentration under reduced pressure, we obtain 62 g of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in the form of brown oil, which is used “as is” in the next stage.

Yield=89%

1.2. (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde

Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H) (355 mmol) in toluene to a solution of 61 g (322 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous toluene under argon and cooled to 0° C., maintaining the temperature at 0° C. Then bring the reaction mixture to room temperature (RT) and stir for 3 h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174 mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir the suspension for one hour, then filter on a celite bed. Wash the filtrate with 500 mL of water then dry over Na₂SO₄ and concentrate under reduced pressure. Take up the residue obtained in 500 mL of DCM and filter in a silica column, eluting with DCM. After concentration under reduced pressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde in the form of colourless oil.

Yield=60%.

1.3. Ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate

Add dropwise, while stirring, a solution of 37 g (192 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde and 85.7 g (664 mmol) of ethyl 2-azidoacetate in 200 mL of absolute ethanol EtOH to a solution of 15.5 g (673 mmol) of sodium in 500 mL of absolute EtOH cooled to −10° C. and kept under argon, maintaining the temperature at −10° C. After stirring at −10° C. for 3 h, stir the reaction mixture for 15 h at RT, then pour into 600 mL of an aqueous solution of ammonium chloride (NH₄Cl) at 30 wt. %. After filtration on a frit and rinsing with 2×200 mL of water, take up the precipitate in 600 mL of DCM, dry over Na₂SO₄ and concentrate under reduced pressure, which leads to 42 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate in the form of a yellow solid.

Yield=80%

M.p. (° C.)=138.

1.4 Ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[triphenylphosphoranylidene)amino]penta-2,4-dienoate

Add, dropwise, a solution of 5 g of ethyl (2E,4E)-2-azido-5-(2,6-dimethoxyphenyl)penta-2,4-dienoate (16.5 mmol) in 60 mL of DCM to a solution of 4.37 g (16.7 mmol) of triphenylphosphine in 40 mL of DCM. Stir the reaction mixture for 2 h at RT, then concentrate under reduced pressure. Solidify the residue obtained in 100 mL of isopropyl ether, then filter on a frit and rinse with 50 mL of isopropyl ether, giving 7.9 g of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate in the form of a white solid.

Yield=91%

M.p. (° C.)=172

1.5. Ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate

Reflux a solution of 7.54 g (14 mmol) of ethyl (2E,4E)-5-(2,6-dimethoxyphenyl)-2-[(triphenylphosphoranylidene)amino]penta-2,4-dienoate and 2.42 g (15.4 mmol) of 4-chloro-3-hydroxybenzaldehyde in 280 mL of anhydrous acetonitrile for 96 h. After cooling to RT, concentrate the reaction mixture under reduced pressure and purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/ethyl acetate (EtOAc) gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 2.4 g of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of white powder.

Yield=41%

M.p. (° C.)=182

1.6. Ethyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxy-phenyl)pyridine-2-carboxylate

Add 0.257 g (2.11 mmol) of 3-chloro-N,N-dimethylpropane-1-amine hydrochloride and 3.40 g (1.34 mmol) of caesium carbonate to a solution of 0.5 g (1.21 mmol) of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 20 mL of anhydrous DMF under argon. Stir the reaction mixture for 15 min at RT then heat for 2 h at 80° C. After cooling to RT, add 1 mL of an aqueous solution of citric acid at 5% and concentrate the whole under reduced pressure. Take up the residue in 50 mL of EtOAc and wash with 10 mL of a 5% solution of Na₂CO₃ and then 10 mL of water. After drying over Na₂SO₄ and concentration under reduced pressure, purify the residue by silica gel column chromatography, eluting with a DCM/methanol gradient from 1 to 15% of methanol. After concentration under reduced pressure, we obtain 0.55 g of ethyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of oil.

Yield=91%

1.7. 6-{4-Chloro-3-[3-(dimethylamino)propoxy-]phenyl}-5-(2,6-dimethoxy-phenyl)pyridine-2-carboxylic acid

Add 3.16 g (56.38 mmol) of potassium hydroxide to a solution of 5.63 g (11.28 mmol) of ethyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 132 mL of EtOH. Reflux the reaction mixture for 2 h and then concentrate under reduced pressure. Take up the residue obtained in 10 mL of water, then neutralize with 56.5 mL (56.5 mmol) of a 1N HCl aqueous solution. The precipitate obtained is filtered on a frit and rinsed with 2×10 mL of water. After drying under reduced pressure, we obtain 5.25 g of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid in the form of white powder.

Yield=100%

M.p. (° C.)=215

1.8. 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid

Add, under argon, 0.74 mL (0.41 mmol) of diisopropylethylamine and 409 mg (1.28 mmol) of TBTU to a solution of 200 mg (0.42 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid in 50 mL of anhydrous DMF. In parallel, heat, while stirring under argon, a mixture of 84 mg (0.59 mmol) of 2-aminocyclohexane-2-carboxylic acid and 0.18 mL (0.76 mmol) of N,O-bis(trimethylsilyl)acetamide (BSA) in 5 mL of anhydrous acetonitrile to 90° C. After 2 h, the mixture has dissolved completely. Cool the solution to RT, then add it to the solution of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2 carboxylic acid activated with TBTU. After stirring for 18 h at RT, add 10 mL of 0.5N HCl aqueous solution and continue stirring for 3 h. Then distribute the reaction mixture in a mixture of 20 mL of EtOAc/ether 1:1 and 10 mL of water. After extraction, extract the aqueous phase again with 10 mL of 1:1 ether/EtOAc mixture. Combine the organic phases, wash with 2×10 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Then purify the residue by reverse-phase HPLC(RP18) eluting with a 0.01N HCl/acetonitrile gradient from 5% to 100% of acetonitrile. After concentration under reduced pressure and lyophilization, we obtain 106 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=41%

M.p. (° C.)>200.

M=C₃₂H₃₈ClN₃O₆=595; M+H=596

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.70 (s, 1H); 7.80 (d, 1H); 7.65 (d, 1H) 7.15 (m, 2H); 7.05 (d, 1H); 6.60 (d, 1H); 6.50 (d, 2H); 3.85 (t, 2H); 3.35 (s, 6H); 2.75 (m, 2H); 2.45 (s, 6H); 2.15 (m, 2H); 1.90 (m, 2H) 1.55 (m, 4H); 1.25 (m, 4H).

EXAMPLE 2 9-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic acid hydrochloride Compound No. 25 2.1. 9-aminobicyclo[3.3.1.]nonane-9-carbonitrile

Add successively 21 mL of water, 1.12 g (22.8 mmol) of sodium cyanide, 4.52 mL (54.27 mmol) of 12N aqueous ammonia solution and 2.32 g (43.41 mmol) of NH₄Cl to a solution of 3 g (21.7 mmol) of bicyclo[3.3.1]nonan-9-one in 40 mL of EtOH. Stir the reaction mixture for 18 h at 50° C. Then add 5 mL of 12N aqueous ammonia solution and heat the mixture again for 4 h at 50° C. Cool the solution to RT then distribute in 100 mL of a 1:1 mixture of ether/1N aqueous soda solution. After extraction, wash the organic phase with 3×50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Take up the residue obtained in 50 mL of ether and then treat for 1 minute with a gentle stream of hydrogen chloride. Filter the hydrochloride thus obtained, wash with 20 mL of ether and distribute in 100 mL of a 1:1 mixture of DCM/saturated aqueous solution of Na₂CO₃. Extract the aqueous phase again with 50 mL of DCM, then combine the organic phases, wash with 2×20 mL of water and dry over Na₂SO₄. After concentration under reduced pressure, we obtain 1.88 g of 9-aminobicyclo[3.3.1]nonane-9-carbonitrile in the form of oil.

Yield=52%

2.2. N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide

Add a solution of 2.37 g (17.17 mmol) of potassium carbonate in 30 mL of water, then 1.37 mL (11.8 mmol) of benzoyl chloride, to a solution of 1.88 g (11.45 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carbonitrile in 20 mL of THF. Stir the reaction mixture for 1 h at RT, then distribute in 100 mL of a 1:1 mixture of DCM/water. Wash the organic phase with 50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Solidify the residue obtained in 100 mL of pentane giving, after filtration and washing with pentane, 2.81 g of N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in the form of white powder.

Yield=92%

M.p. (° C.)>200

2.3. 9-Aminobicyclo[3.3.1]nonane-9-carboxylic acid

Add 200 mL of a 12N HCl aqueous solution to a solution of 2.8 g (10.43 mmol) of N-(9-cyanobicyclo[3.3.1]non-9-yl)benzamide in 80 mL of THF. Stir the solution for 20 h at RT—a white precipitate gradually appears. After filtering the precipitate on a frit and rinsing with 3×200 mL of water, we obtain 3.6 g of wet 9-benzoylamino bicyclo[3.3.1]nonane-9-carboxylic acid.

Dissolve 3 g (10.44 mmol) of 9-benzoylamino bicyclo[3.3.1]nonane-9-carboxylic acid in 200 mL of AcOH and 50 mL of 6N HCl aqueous solution, reflux the mixture for 18 h and then concentrate partially by distillation of 150 mL of solvent. After cooling, filter the reaction mixture and distribute in 150 mL of a 1:2 mixture of 1N HCl aqueous solution/ether. After extraction, concentrate the aqueous phase and then treat it dropwise with a 12N aqueous solution of soda (NaOH) to adjust the pH to 5-6. Filter the amino acid thus precipitated, wash with 3×50 mL of water and dry under reduced pressure, which gives 1.88 g of 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid in the form of white crystals.

Yield=98%

M.p. (° C.)>250.

2.4. 9-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic acid hydrochloride

According to the method described in example 1.8, starting from 400 mg (0.85 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid and 218 mg (1.19 mmol) of 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid and after reverse-phase purification and lyophilization, we obtain 220 mg of 9-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)bicyclo[3.3.1]nonane-9-carboxylic acid hydrochloride in the form of white powder.

Yield=41%

M.p. (° C.): 197

M=C₃₅H₄₂ClN₃O₆=635; M+H=636

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.45 (s, 1H); 8.00 (d, 1H); 7.80 (d, 1H); 7.30 (t, 2H); 7.25 (s, 1H); 7.05 (d, 1H); 6.95 (dd, 1H); 6.70 (d, 1H); 3.85 (t, 2H); 3.50 (s, 6H); 3.05 (m, 2H); 2.70 (s, 6H); 2.2-1.4 (m, 16H).

EXAMPLE 3 2-({[6-{4-Chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride Compound No. 15 3.1. Ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate

Add 88 mg (0.87 mmol) of 1-methyl-3-hydroxypyrrolidine, 246 mg (1.09 mmol) of triphenylphosphine and 0.01 mL (0.07 mmol) of TEA to a solution of 300 mg (0.72 mmol) of ethyl 6-(4-chloro-3-hydroxyphenyl)-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in 2.5 mL of anhydrous THF cooled to 0° C. and placed under argon. After dissolution, add dropwise, at 0° C., a solution of 0.24 mL (1.09 mmol) of DIAD in 2.5 mL of anhydrous THF. Bring the reaction mixture to RT, stir for 18 h, then take up in 50 mL of EtOAc. Wash the organic phase successively with 20 mL of a saturated aqueous solution of sodium bicarbonate (NaHCO₃) then 20 mL of water. After drying over Na₂SO₄ and concentration under reduced pressure, purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 20% of methanol. After concentration under reduced pressure, we obtain 250 mg of ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate in the form of oil.

Yield=70%

3.2. 2-({[6-{4-Chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 250 mg (0.5 mmol) of ethyl 6-{4-chloro-3-[(1-methylpyrrolidin-3-yl)oxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylate and 100 mg (0.51 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 160 mg of 2-({[6-{4-chloro-3-[2-(dimethylamino)ethoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid in the form of white powder.

Yield=47%

M.p. (° C.)=215

M=C₃₆H₄₀ClN₃O₆=645; M+H=646

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.40 (s, 1H); 8.00 (d, 1H); 7.85 (d, 1H); 7.35 (m, 2H); 7.05 (dd, 1H); 6.95 (t, 1H); 6.65 (d, 2H); 4.90 (m, 1H); 3.80 (m, 2H); 3.50 (s, 6H); 3.15 (m, 2H); 2.85 (m, 3H); 2.55 (s, 2H); 2.2-1.6 (m, 14H).

EXAMPLE 4 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride Compound No. 18

Methyl 6-bromo-5-hydroxy-2-pyridine carboxylate is synthesized according to a method already described in the literature (J. Org. Chem., 1996, 4623-4633).

4.1. 2-(benzyloxy)-1-chloro-4-iodobenzene

A suspension of 300 g (1179 mmol) of 2-chloro-5-iodophenol and 140 mL (1179 mmol) of benzyl bromide and 195.5 g (1415 mmol) of anhydrous potassium carbonate in 1.2 L of anhydrous DMF is stirred for 5 h at 70° C. and then cooled to RT. The reaction mixture is then distributed in 3 L of a 2:1 ether/water mixture. The organic phase is washed with 2×1 L of water, dried over Na₂SO₄, concentrated under reduced pressure and the residue obtained is solidified in pentane. We thus obtain 376 g of 2-(benzyloxy)-1-chloro-4-iodobenzene in the form of beige powder.

Yield=92%

M.p. (° C.)=72.

4.2. [3-(Benzyloxy)-4-chlorophenyl]boronic acid

Add dropwise 374 mL (748 mmol) of a solution of iPrMgCl 2N in THF to a solution of 198 g (575 mmol) of 2-(benzyloxy)-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF under argon and stirred at −50° C., maintaining the temperature between −40 and −50° C. Allow the reaction mixture to return to −10° C. and continue stirring for 1 h. Then add 172 mL (748 mmol) of triisopropyl borate and leave the reaction mixture to return slowly to RT. After stirring for 2 h, treat the mixture with 1 L of aqueous solution of HCl 5N, then extract with ether (2×600 mL). Wash the organic phase with 2×1 L of water, dry over Na₂SO₄ then concentrate under reduced pressure. Solidify the residue obtained in pentane, filter on a frit and wash with pentane. We thus obtain 113 g of [3-(benzyloxy)-4-chlorophenyl]boronic acid in the form of a white solid.

Yield=76%

M.p. (° C.)=148 (decomposition).

4.3. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate

Stir a solution of 37 g (163 mmol) of methyl 6-bromo-5-hydroxy-2-pyridine carboxylate and 51 g (196 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid in 300 mL of anhydrous DMF for 15 min while bubbling with argon, then add 63.8 g (196 mmol) of anhydrous caesium carbonate and 5 g (4.33 mmol) of Pd(PPh₃)₄. Stir the reaction mixture for 10 h at 90° C. under argon, cool to RT, then distribute in 1 L of ether/EtOAc 1:1 mixture and 1 L of a 0.5N aqueous HCl solution. Extract the aqueous phase again with 500 mL of EtOAc/ether 1:1 mixture. Combine the organic phases and wash with 4×500 mL of water. After drying over Na₂SO₄ and concentration under reduced pressure, take up the precipitate with 500 mL of a 7:3 mixture of pentane/DCM, filter and wash with pentane. We thus obtain 32 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate in the form of yellow ochre powder.

Yield=53%

M.p. (° C.)=202

4.4. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate

Add 17.7 mL (126 mmol) of TEA to a mixture of 38.8 g (105 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-hydroxypyridine-2-carboxylate in 200 mL of DCM. The mixture dissolves gradually and is cooled to −5° C. under argon. Add, dropwise, 19.42 mL (115.4 mmol) of trifluoromethanesulphonic anhydride, maintaining the temperature at 0° C. After 3 h at 0° C., take up the reaction mixture in 300 mL of DCM and wash with 2×200 mL of water, dry over Na₂SO₄, then concentrate under reduced pressure. Purify the residue obtained by chromatography on a silica column, eluting with a pentane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 47.5 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate in the form of white crystals.

Yield=90%

M.p. (° C.)=89.

4.5. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

Stir a solution of 25 g (48.8 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate and 8.8 g (64.8 mmol) of 2-methylphenylboronic acid in 200 mL of anhydrous DMF for 15 min while bubbling with argon, then add 12.7 g (60 mmol) of anhydrous potassium phosphate (K₃PO₄) and 5.76 g (5 mmol) of Pd(PPh₃)₄ and stir the reaction mixture for 18 h at 90° C. under argon. Then distribute the reaction mixture at RT in 600 mL of ether/EtOAc 1:1 mixture and 600 ml of water. After extraction, extract the aqueous phase again with 100 mL of EtOAc, combine the organic phases and wash with 4×300 mL of water, dry over Na₂SO₄, then concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 18 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of oil.

Yield=81%

4.6. Methyl 6-(4-chloro-3-hydroxy]phenyl)-5-(2-methylphenyl)pyridine-2-carboxylate

Add dropwise, in 1 h 30 min, 85.6 mL (85.6 mmol) of a 1N solution of boron tribromide in DCM to a solution of 19 g (42.8 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in 70 mL of anhydrous DCM cooled under argon to −70° C., maintaining the temperature at −65° C. After stirring for 2 h at −70° C., add dropwise 20 mL (520 mmol) of anhydrous methanol, maintaining the temperature at −65° C. Bring the reaction mixture to RT, then concentrate under reduced pressure. Take up the residue in 100 mL of toluene and concentrate again. Repeat the operation two more times. Take up the residue obtained in 100 mL of methanol and cool under argon at 0° C., then add dropwise 9 mL (128 mmol) of thionyl chloride. Stir the reaction mixture for 48 h at RT, then concentrate under reduced pressure. Take up the residue obtained in 200 mL of EtOAc, cool to 0° C. and treat with 300 mL of a saturated aqueous solution of NaHCO₃. After extraction, extract the aqueous phase again with 100 mL of EtOAc. Combine the organic phases, wash with 100 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 14.7 g of methyl 6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate in the form of white powder.

Yield=97%

M.p. (° C.)=190

4.7. Methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate

According to the method described in example 1.6, starting from 5.4 g (15.26 mmol) of methyl 6-(4-chloro-3-hydroxyphenyl)-5-(2-methylphenyl)pyridine-2-carboxylate, 9.95 g (30.53 mmol) of caesium carbonate and 2.9 g (18.3 mmol) of 3-chloro-N,N-dimethylpropan-1-amine hydrochloride in 60 mL of DMF, we obtain 6 g of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate in the form of oil.

Yield=90%

4.8. 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 4.65 g (10.6 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate and 2.38 g (12.18 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 4.1 g of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.

Yield=54%

M.p. (° C.): 224.

M=C₃₅H₄₀ClN₃O₄=601; M+H=602

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.05 (d, 1H); 7.90 (d, 1H); 7.25 (m, 5H); 7.10 (dd, 1H); 6.95 (dd, 1H); 3.80 (m, 2H); 3.1 (m, 2H); 2.75 (s, 6H); 2.60 (s, 2H); 1.90 (s, 3H); 2.2-1.6 (m, 14H).

EXAMPLE 5 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride Compound No. 23 5.1. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate

Stir a solution of 500 mg (1 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate, 0.1 mL (1.1 mmol) of 2-pyrrolidinone and 450 mg (1.4 mmol) of caesium carbonate in 10 mL of anhydrous 1,4-dioxan for 10 minutes while bubbling with argon, then add 9 mg (0.01 mmol) of Pd₂(dba)₃ and 17 mg (0.03 mmol) of Xantphos and heat the reaction mixture for 6 h at 70° C. while stirring. Then distribute the mixture in 100 mL of ether/EtOAc 1:1 mixture and 50 mL of a saturated aqueous solution of NH₄Cl. After extraction, wash the organic phase with 2×50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 293 mg of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate in the form of oil.

Yield=67%.

5.2. Methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 511 mg (1.17 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate, we obtain 391 mg of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate in the form of oil.

Yield=77%

5.3. 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 391 mg (0.91 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridine-2-carboxylate and 265 mg (1.36 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 241 mg of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.

Yield=39%

M.p. (° C.): 199

M=C₃₂H₃₉ClN₄O₅=594; M+H=595

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.40 (s, 1H); 8.05 (t, 2H); 7.55 (d, 1H); 7.50 (s, 1H); 7.20 (dd, 1H); 4.15 (t, 2H); 3.65 (t, 2H); 2.75 (s, 6H); 2.55 (s, 2H); 2.2-1.6 (m, 20H).

EXAMPLE 6 2-{[(2′-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic acid hydrochloride Compound No. 27 6.1. Methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate

Stir a suspension of 0.5 g (1 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate, 0.44 g (1.2 mmol) of 2-tri-n-butylstannylpyridine and 42 mg (1 mmol) of anhydrous lithium chloride in 2 mL of anhydrous DMF for 10 min while bubbling with argon, then add 9.5 mg (0.05 mmol) of CuI, 45 mg (0.05 mmol) of Pd₂(dba)₃ and 27 mg (0.05 mmol) of PdCl₂ (dppf) and then heat the reaction mixture to 90° C. After stirring for 5 h at 90° C., cool the mixture to RT, take up in 30 ml of EtOAc, treat and stir for 15 minutes with 30 mL of a 5 wt. % aqueous solution of potassium fluoride. Then filter the two-phase mixture on a bed of celite, and rinse the celite with 30 mL of EtOAc. Wash the organic phase with 4×60 mL of water, dry over Na₂SO₄ and concentrate at reduced pressure. Purify the residue obtained by chromatography on a silica column, eluting with a toluene/EtOAc gradient from 0 to 15% of EtOAc. After concentration under reduced pressure, we obtain 240 mg of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate in the form of oil.

Yield=55%

6.2. Methyl 2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 680 mg (1.58 mmol) of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-2,3′-bipyridine-6′-carboxylate, we obtain 580 mg of methyl 2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate in the form of oil.

Yield=86%

6.3. 2-{[(2′-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 581 mg (1.36 mmol) of methyl 2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate and 365 mg (1.87 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 435 mg of 2-{[(2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}adamantane-2-carboxylic acid hydrochloride in the form of white powder.

Yield=48%

M.p. (° C.): 209

M=C₃₃H₃₇ClN₄O₄=588; M+H=589

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.55 (s, 1H); 8.65 (s, 1H); 8.50 (s, 1H); 8.25 (d, 1H); 8.10 (d, 1H); 7.80 (t, 1H); 7.40 (dd, 1H); 7.35 (d, 2H); 7.25 (s, 1H); 6.80 (d, 1H); 3.95 (t, 2H); 3.15 (m, 2H); 2.75 (s, 3H); 2.70 (s, 3H); 2.60 (s, 2H); 2.2-1.6 (m, 14H).

EXAMPLE 7 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride Compound No. 22 7.1. Methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 625 mg (1.35 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-chlorophenyl)pyridine-2-carboxylate, we obtain 173 mg of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylate in the form of oil.

Yield=28%

7.2. 2-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 290 mg (0.63 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridine-2-carboxylate and 184 mg (0.94 mmol) of 2-aminoadamantane-2-carboxylic acid, we obtain 120 mg of 2-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chlorophenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.

Yield=29%

M.p. (° C.): 214

M=C₃₄H₃₇Cl₂N₃O₄=621; M+H=622

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.10 (d, 1H); 8.00 (d, 1H); 7.45 (m, 2H); 7.40 (d, 2H); 7.35 (d, 1H); 7.20 (dd, 1H); 6.90 (dd, 1H); 3.90 (m, 2H); 3.15 (m, 2H); 2.75 (s, 6H); 2.60 (s, 2H); 2.2-1.6 (m, 14H).

EXAMPLE 8 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 34

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 465 mg (1.06 mmol) of methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylate (example 4.7) and 174 mg (1.22 mmol) of 2-aminocyclohexane-2-carboxylic acid, we obtain 330 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=53%

M.p. (° C.)=146-150

M=C₃₁H₃₆ClN₃O₄=549; M+H=550

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.5 (s, 1H); 8.40 (s, 1H); 8.05 (d, 1H); 7.90 (d, 1H); 7.35 (d, 1H); 7.25 (m, 5H); 7.05 (dd, 1H); 3.80 (m, 2H); 3.1 (m, 2H); 2.75 (s, 6H); 1.75 (s, 3H); 2.2-1.6 (m, 12H).

EXAMPLE 9 cis-1-({[6-{4-Chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexane carboxylic acid hydrochloride Compound No. 147

Add successively, under argon and at RT, 127 mg (1.1 mmol) of N-hydroxysuccinimide and 211 mg (1.1 mmol) of EDC.HCl to a mixture of 490 mg (1 mmol) of 6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridine-2-carboxylic acid hydrochloride in 5 mL of anhydrous DMF. After stirring for 18 h, add successively to the (bright yellow, clear) reaction mixture, 0.9 mL (5.4 mmol) of DIEA and 215 mg (1.1 mmol) of cis-1-amino-4-hydroxycyclohexane carboxylic acid (J. Chem. Soc., Perkin Trans. 1 (1999) pp. 3375-3379). Continue stirring for 18 h at RT, then concentrate the reaction mixture under reduced pressure. Then treat the residue obtained for 18 h at RT with 7 mL (7 mmol) of 1N HCl, then concentrate under reduced pressure. Purify the residue by HPLC on a column of RP18, eluting with a 10⁻²N HCl/acetonitrile gradient from 0% to 100% of acetonitrile. After lyophilization, we obtain 350 mg of cis-1-({[6-{4-chloro-3-[3-(diethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-hydroxycyclohexane carboxylic acid hydrochloride in the form of white powder.

Yield=55%

M.p. (° C.)=168

M=C₃₃H₄₀ClN₃O₅=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.55 (s, 1H); 8.05 (d, 1H); 7.90 (d, 1H); 7.25 (m, 6H); 6.90 (dd, 1H); 4.65 (sl, 1H); 3.90 (m, 2H); 3.50 (m, 1H); 3.10 (m, 2H); 2.95 (q, 4H); 2.30 (m, 2H); 2.05 (m, 2H); 1.90 (s, 3H); 1.80 (m, 4H); 1.35 (m, 2H); 1.10 (t, 6H)

EXAMPLE 10 3-[({4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic acid hydrochloride Compound No. 28 10.1.2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Stir a suspension of 20 g (67.2 mmol) of 2-benzyloxy-4-bromo-1-chlorobenzene, 28 g (94 mmol) of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane and 26.4 g (26.9 mmol) of potassium acetate in 280 mL of anhydrous DMSO for 10 minutes under argon, then add 2.46 g (3.4 mmol) of PdCl₂ (dppf) and heat for 1 h at 110° C. After distributing in 1 L of a 1:1 ether/water mixture and filtering on a bed of celite, wash the organic phase with 100 mL of water, dry over Na₂SO₄, then concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 17.5 g of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the form of oil.

Yield=74%.

10.2. Methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate

Stir a solution of 4.84 g (14.2 mmol) of methyl 3-bromo-4-iodobenzoate (J. Med. Chem., 1999, 42, 4088) and 3.88 g (21.29 mmol) of 2,6-dimethoxyphenyl boronic acid in 120 mL of DMF and 14.2 mL of a 2M aqueous solution of caesium carbonate for 15 minutes under argon, then add 984 mg (0.85 mmol) of Pd(PPh₃)₄ and heat for 2.5 h at 85° C. After concentration under reduced pressure, distribute the residue obtained in 600 mL of a 1:1 DCM/water mixture. Wash the organic phase with 100 mL of water, dry over MgSO₄ and concentrate at reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 2.79 g of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate in the form of oil.

Yield=56%

10.3. Methyl 3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate

According to the method described in example 10.2, starting from 2.79 g (7.94 mmol) of methyl 2-bromo-2′,6′-dimethoxybiphenyl-4-carboxylate and 3.28 g (9.53 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, we obtain 1.75 g of methyl 3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate in the form of oil.

Yield=45%

10.4. Methyl 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 1.75 g (3.58 mmol) of methyl 3″-(benzyloxy)-4″-chloro-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate, we obtain 900 mg of methyl 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate in the form of oil.

Yield=52%

10.5. 4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylic acid

According to the method described in example 1.7, starting from 900 mg (1.86 mmol) of methyl 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylate, we obtain 700 mg of 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylic acid in the form of a pinkish solid.

Yield=82%

M.p. (° C.)=230.

10.6. 3-[({4″-Chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic acid hydrochloride

Add 141 mg (0.87 mmol) of CDI to a solution of 315 mg (0.67 mmol) of 4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-carboxylic acid in 7 mL of anhydrous THF, and stir the reaction mixture at 55° C. for 1 h under argon. Add 70 mg (0.43 mmol) of carbonyl-1,1′-diimidazole and continue the reaction for 1 h at 50° C. Then add a suspension of 97 mg (0.74 mmol) of racemic 3-amino-4-methylpentanoic acid in a mixture of 4 mL of THF and 0.8 mL of DMF and continue stirring for 15 h at 55° C. After concentration under reduced pressure, distribute the residue obtained in 30 mL of a 2:1 DCM/water mixture. Wash the organic phase with 10 mL of water, dry over magnesium sulphate (MgSO₄) and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 5% of methanol. After concentration under reduced pressure, solidify the residue in ether, filter on a frit and wash with ether. We thus obtain 91 mg of 3-[({4″-chloro-3″-[3-(dimethylamino)propoxy]-2,6-dimethoxy-1,1′:2′,1″-terphenyl-4′-yl}carbonyl)amino]-4-methylpentanoic acid hydrochloride in the form of white powder.

Yield=23%

M.p. (° C.)=152

M=C₃₂H₃₉ClN₂O₆=582; M+H=583

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.3 (d, 1H); 7.75 (d, 1H); 7.7 (s, 1H); 7.2 (m, 3H); 6.7 (m, 2H); 6.55 (d, 2H); 4.1 (q, 1H) 3.8 (t, 2H); 3.5 (s, 6H); 2.45 (m, 4H); 2.3 (s, 6H) 1.8 (m, 3H); 0.9 (d, 6H).

EXAMPLE 11 3-({[5-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride Compound 29 11.1. Methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate

Stir a solution of 4 g (14.35 mmol) of methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate and 6.42 g (18.64 mmol) of 2-[3-(benzyloxy)-4-chlorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a mixture of 160 mL of dimethoxyethane (DME), 80 mL of EtOH and 120 mL of a saturated aqueous solution of NaHCO₃ for 15 minutes under argon, then add 662 mg of Pd(PPh₃)₄ and heat the reaction mixture for 4 h 30 min at 90° C. After concentration under reduced pressure, distribute the residue obtained in a mixture of 200 mL of DCM and 10 mL of water. Extract the aqueous phase again with 100 mL of DCM, combine the organic phases, dry over MgSO₄, filter and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 2% of methanol. After concentration under reduced pressure, solidify the residue in a 5/95 methanol/ether mixture, then filter and wash with ether. We thus obtain 1.99 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate in the form of a beige solid.

Yield=40%

M.p. (° C.): 190

11.2. Methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate

According to the method described in example 4.4, starting from 1.99 g (5.38 mmol) of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-oxo-1,6-dihydropyridine-3-carboxylate and 2.26 ml (13.45 mmol) of trifluoromethanesulphonic anhydride, we obtain 1.6 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate in the form of oil.

Yield=60%

11.3. Methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate

According to the method described in example 4.5, starting from 1.5 g (2.99 mmol) of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-{[(trifluoromethyl)sulphonyl]oxy}nicotinate and of 508 mg (3.74 mmol) of 2-methylphenyl boronic acid, we obtain 1.26 g of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate in the form of oil.

Yield=95%

11.4. Methyl 5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 1.26 g (2.84 mmol) of methyl 5-[3-(benzyloxy)-4-chlorophenyl]-6-(2-methylphenyl)nicotinate, we obtain 843 mg of methyl 5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinate in the form of oil.

Yield=68%

11.5. 3-({[5-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 10.6 respectively, starting from 835 mg (1.90 mmol) of methyl 5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinate and 258 mg (1.97 mmol) of racemic 3-amino-4-methylpentanoic acid, we obtain 130 mg of 3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride in the form of a white solid.

Yield=13%

M.p. (° C.)=139

M=C₃₀H₃₆ClN₃O₄=537; M+H=538

¹H NMR (ppm, d6-DMSO, 400 MHz): 9.05 (d, 1H); 9.5 (d, 1H); 9.25 (d, 1H); 8.3 (d, 1H); 7.3 (d, 1H) 7.15 (d, 1H); 7.15 (m, 4H); 4.25 (m, 1H); 3.8 (t, 2H); 2.65 (t, 2H); 2.45 (s, 6H) 1.95 (s, 3H); 1.85 (m, 5H); 0.90 (d, 6H).

EXAMPLE 12 2-({[6-[3-[3-(Dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride Compound No. 43 12.1. 2-iodo-5-nitrophenol

Add, dropwise, a solution of 20.7 g (300 mmol) of sodium nitrite (NaNO₂) in 100 mL of water to a solution of 30.81 g (200 mmol) of 2-amino-5-nitrophenol in a mixture of 500 mL of sulphuric acid at 30 wt. % and 500 mL of DMSO cooled to 5° C., maintaining the temperature at 5° C. After 30 min at 5° C., add dropwise a solution of 90 g (600 mmol) of sodium iodide in 100 mL of water, then bring the reaction mixture up to RT. After stirring for 2 h, distribute the reaction mixture in 2 L of a mixture of ether/aqueous solution at 10 wt. % of sodium bisulphite 1:1. Extract the aqueous phase again with 200 mL of ether, combine the organic phases and wash with 3×1 L of water, then dry over Na₂SO₄. After concentration under reduced pressure, purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 10% of EtOAc. After concentration under reduced pressure, we obtain 39.8 g of 2-iodo-5-nitrophenol in the form of a brown solid.

Yield=75%

M.p. (° C.)=150

12.2. 2-(benzyloxy)-1-iodo-4-nitrobenzene

According to the method described in example 4.1., starting from 20.8 g (78.5 mmol) of 2-iodo-5-nitrophenol and 9.3 mL (78.5 mmol) of benzyl bromide, we obtain 25.2 g of 2-(benzyloxy)-1-iodo-4-nitrobenzene in the form of oil.

Yield=90%

12.3. 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene

Add 10.4 mL (70.18 mmol) of trifluoromethyltrimethylsilane to a mixture of 4.08 g (70.2 mmol) of anhydrous potassium fluoride and 13.36 g (70.18 mmol) of anhydrous CuI and 19.17 g (54 mmol) of 2-(benzoxy)-1-iodo-nitrobenzene in 77 mL of anhydrous NMP, and heat the reaction mixture for 18 h at 45° C. under argon. Distribute the suspension at RT in 1 L of a 1:1 ether/water mixture, then wash the organic phase with 4×300 mL of water, dry over Na₂SO₄, and concentrate under reduced pressure. We thus obtain 15 g of 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene in the form of oil.

Yield=94%

12.4. 3-(benzyloxy)-4-(trifluoromethyl)aniline

Add 14.1 g (252 mmol) of iron filings to a mixture of 15 g (50.3 mmol) of 2-(benzyloxy)-4-nitro-1-(trifluoromethyl)benzene in 200 mL of EtOH, 10 mL of AcOH and 100 mL of water, then stir the reaction mixture vigorously at 70° C. for 20 minutes. After cooling to RT, slowly add the reaction mixture to a mixture of 300 mL of ether and 1 L of a saturated aqueous solution of Na₂CO₃. After neutralizing, extract the aqueous phase again with 2×100 mL of ether. Combine the organic phases, wash with 100 mL of water, dry over calcium chloride and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a pentane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 8.1 g of 3-(benzyloxy)-4-(trifluoromethyl)aniline in the form of oil.

Yield=60%

12.5. 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene

According to the method described in example 12.1., starting from 8 g (30 mmol) of 3-(benzyloxy)-4-(trifluoromethyl)aniline, we obtain 8 g of 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene in the form of oil.

Yield=70%

12.6. [3-(Benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid

According to the method described in example 4.2, starting from 8 g (21.2 mmol) of 2-(benzyloxy)-4-iodo-1-(trifluoromethyl)benzene, 11.1 mL (22.2 mmol) of iPrMgCl and 5 mL (21.6 mmol) of triisopropyl borate, we obtain 4.95 g of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid in the form of oil.

Yield=79%

12.7. Methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate

According to the method described in example 4.3, starting from 4.95 g (16.7 mmol) of [3-(benzyloxy)-4-(trifluoromethyl)phenyl]boronic acid and 3.88 g (16.72 mmol) of methyl 6-bromo-5-hydroxypyridine-2-carboxylate, we obtain 4.38 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate in the form of a white solid.

Yield=65%

M.p. (° C.)=82

12.8. Methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

According to the triflate/Suzuki coupling steps described in examples 4.4 and 4.5 respectively, starting from 4.38 g (10.9 mmol) of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-carboxylate and 1.8 g (13.1 mmol) of 2-methylphenylboronic acid, we obtain 4.63 g of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of a white solid.

Yield=89%

M.p. (° C.)=226

12.9. Methyl 6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 2.57 g (5.38 mmol) of methyl 6-[3-(benzyloxy)-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate, we obtain 2.26 g of methyl 6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate in the form of a white solid.

Yield=89%

M.p. (° C.)=142

12.10. 2-({[6-[3-[3-(Dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 565 mg (1.19 mmol) of methyl 6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridine-2-carboxylate and 256 mg (1.31 mmol) of 2-amino-adamantane-2-carboxylic acid, we obtain 440 mg of 2-({[6-[3-[3-(dimethylamino)propoxy]-4-(trifluoromethyl)phenyl]-5-(2-methylphenyl)pyridin-2-yl]carbonyl}amino)adamantane-2-carboxylic acid hydrochloride in the form of white powder.

Yield=55%

M.p. (° C.)=231

M=C₃₆H₄₀F₃N₃O₄=634; M+H=635

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.50 (s, 1H); 8.10 (d, 1H); 7.95 (d, 1H); 7.55 (d, 1H); 7.25 (m, 5H); 7.10 (d, 1H); 3.90 (m, 2H); 3.05 (m, 2H); 2.70 (s, 6H); 2.60 (s, 2H); 2.05 (m, 7H); 1.90 (s, 3H); 1.65 (m, 7H).

EXAMPLE 13 1-{[(3-Chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexane carboxylic acid hydrochloride Compound No. 55 13.1. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate

Stir a solution of 5 g (10 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate and 2.78 g (11 mmol) of 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane in 50 mL of anhydrous 1,4-dioxan for 15 min while bubbling with argon, then add 2.93 g (30 mmol) of anhydrous potassium acetate and 0.37 g (0.45 mmol) of PdCl₂(dppf) and heat the reaction mixture for 26 h at 80°. Then distribute the reaction mixture in 100 mL of EtOAc/brine 1:1 mixture. Dry the organic phase over Na₂SO₄, filter, and then concentrate under reduced pressure. Purify the residue obtained by chromatography on a silica column, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 3.2 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate in the form of a wax.

Yield=67%

13.2. Methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate

Stir a solution of 850 mg (1.77 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 524 mg (3.54 mmol) of 2,3-dichloropyridine in a mixture of 4 mL of DME and 2 mL of water for 15 minutes under argon, then add successively 734 mg (5.32 mmol) of K₂CO₃ and 61 mg (0.05 mmol) of Pd(PPh₃)₄ and heat the reaction mixture for 4 h at 85° C. Then distribute the reaction mixture between 10 mL of EtOAc and 10 mL of brine. Dry the organic phase over Na₂SO₄, filter, and then concentrate under reduced pressure. Purify the residue obtained on a silica column, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 237 mg of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate in the form of oil.

Yield=28%

13.3. Methyl 3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 360 mg (0.77 mmol) of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3-chloro-2,3′-bipyridine-6′-carboxylate, we obtain 130 mg of methyl 3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate in the form of oil.

Yield=37%

13.4. 1-{[(3-Chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexane carboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 130 mg (0.28 mmol) of methyl 3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate and 44 mg (0.31 mmol) of 2-aminocyclohexanecarboxylic acid, we obtain 120 mg of 1-{[(3-chloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexane carboxylic acid hydrochloride in the form of white powder.

Yield=70%

M.p. (° C.)=140

M=C₂₉H₃₂Cl₂N₄O₄=570; M+H=571

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.45 (s, 1H); 8.65 (d, 1H); 8.45 (s, 1H); 8.10 (s, 2H); 7.95 (d, 1H); 7.50 (dd, 1H); 7.35 (d, 1H); 7.25 (d, 1H); 6.90 (dd, 1H); 3.95 (t, 2H); 3.15 (m, 2H); 2.80 (d, 6H); 2.20 (m, 4H); 1.80 (t, 2H); 1.70-1.2 (m, 6H).

EXAMPLE 14 (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride Compound No. 72 14.1. Methyl 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 743 mg (1.55 mmol) of 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate, we obtain 530 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate in the form of oil.

Yield=72%

14.2. (3S)-3-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 9 respectively, starting from 385 mg (0.84 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridine-2-carboxylate and 130 mg (1 mmol) of (3S)-3-amino-4-methylpentanoic acid (J. Org. Chem., 1999, 6411-6417), we obtain 333 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-methylphenyl)pyridin-2-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride in the form of white powder.

Yield=67%

M.p. (° C.)=157

[α]_(D) ²²=−18°; (c=0.1; MeOH)

M=C₃₀H₃₅Cl₂N₃O₄=571; M+H=572

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.60 (dd, 1H); 8.10 (d, 1H); 7.95 (d, 1H); 7.40-7.15 (m, 5H); 6.90 (d, 1H); 4.15 (m, 1H); 3.90 (m, 2H); 3.15 (t, 2H); 2.75 (s, 6H); 2.55 (t, 2H); 2.25 (d, 3H (conformers)); 2.10 (m, 2H); 1.90 (m, 1H); 0.85 (dd, 6H (conformers)).

EXAMPLE 15 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 66 15.1. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylate

According to the method described in example 4.5, Suzuki coupling effected between 1 g (2 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate and 418 mg (2.8 mmol) of 2,4-dimethylphenylboronic acid leads to 820 mg of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylate in the form of oil.

Yield=90%

15.2. 6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylic acid hydrochloride

According to the debenzylation/O-alkylation/saponification steps described in examples 4.6, 1.6 and 1.7 respectively, starting from 820 mg (1.8 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2,4-dimethylphenyl)pyridine-2-carboxylate, we obtain 659 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylic acid hydrochloride in the form of gum.

Yield=77%

15.3. 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

According to the method described in example 1.8, peptide coupling effected between 356 mg (0.75 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylic acid hydrochloride and 113 mg (0.79 mmol) of 2-aminocyclohexane-2-carboxylic acid leads to 160 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=38%

M.p. (° C.)=158

M=C₃₂H₃₈ClN₃O₄=563; M+H=564

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.45 (s, 1H); 10.40 (s, 1H); 8.45 (s, 1H); 8.05 (d, 1H); 7.95 (d, 1H); 7.40 (d, 1H); 7.20 (s, 1H); 7.15 (s, 2H); 2.75 (s, 6H); 7.10 (d, 1H); 7.05 (d, 1H); 3.90 (m, 2H); 3.20 (t, 2H); 2.70 (s, 6H); 2.35 (s, 3H); 2.2-2.05 (m, 4H); 1.90 (s, 3H); 1.85 (t, 2H); 1.75-1.30 (m, 6H).

EXAMPLE NO. 16 (3S)-3-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride Compound No. 117

According to the method described in example 9, peptide coupling effected between 950 mg (2 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridine-2-carboxylic acid hydrochloride and 412 mg (2.05 mmol) of tert-butyl (3S)-3-amino-4,4-dimethylpentanoate (J. Org. Chem., 1999, 64, 6411-6417) leads to 830 mg of (3S)-3-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,4-dimethylphenyl)pyridin-2-yl]carbonyl}amino)-4,4-dimethylpentanoic acid hydrochloride in the form of white powder.

Yield=70%

M.p. (° C.)=130

[α]_(D) ²²=−5°; (c=0.1; MeOH)

M=C₃₂H₄₀ClN₃O₄=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.09 (s, 1H); 8.2 (d, 1H); 7.85 (d, 1H); 7.70 (d, 1H); 7.10 (d, 1H); 6.95 (d, 1H); 6.85 (m, 3H); 6.80 (t, 1H); 4.10 (t, 1H); 3.65 (m, 2H); 2.95 (m, 2H); 2.50 (d, 6H); 2.40 (dd, 1H); 2.30 (dd, 1H); 2.10 (s, 3H); 1.85 (m, 2H); 1.65 (s, 3H); 0.70 (d, 9H, conformers).

EXAMPLE NO. 17 1-{[(3,5-Dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride Compound No. 65 17.1. Methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate

According to the method described in example 13.2, Suzuki-Myaura coupling effected between 4.4 g (9.17 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate and 2.5 g (11 mmol) of 2-bromo-3,5-dichloropyridine leads to 3 g of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate in the form of oil.

Yield=65%

17.2. Methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3-bipyridine-6′-carboxylate

According to the debenzylation/O-alkylation steps described in examples 4.6 and 1.6 respectively, starting from 3 g (6.2 mmol) of methyl 2′-[3-(benzyloxy)-4-chlorophenyl]-3,5-dichloro-2,3′-bipyridine-6′-carboxylate, we obtain 1.8 g of methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate in the form of gum.

Yield=58%

17.3. 1-{[(3,5-Dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride

According to the saponification/peptide coupling steps described in examples 1.7 and 1.8 respectively, starting from 1.8 g (3.62 mmol) of methyl 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylate and 472 mg (3.3 mmol) of 2-aminocyclohexane-2-carboxylic acid, we obtain 1.12 g of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=50%

M.p. (° C.)=165

M C₂₉H₃₁Cl₃N₄O₄=604; M+H=605

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.75 (s, 1H); 8.45 (s, 1H); 8.30 (d, 1H); 8.15 (dd, 2H); 7.35 (d, 1H); 7.30 (s, 1H); 6.75 (dd, 1H); 4.00 (t, 2H); 3.20 (m, 2H); 2.75 (d, 6H); 2.3-1.3 (m, 12H).

EXAMPLE NO. 18 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 75 18.1. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate

Put 2 g (4 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate in 10 mL of anhydrous toluene in a screw-top bottle. To the solution, under argon, add successively 938 mg (4.78 mmol) of benzophenone hydrazone, 1.95 g (6 mmol) of caesium carbonate and 65 mg (0.08 mmol) of PdCl₂ (dppf). Heat the reaction mixture for 3 h at 90° C. while stirring, then distribute in 100 mL of ether/water 1:1 mixture. Dry the organic phase over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/acetone gradient from 0 to 5% of acetone. After concentration under reduced pressure, we obtain 1.94 g of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate in the form of oil.

Yield=88%

18.2. Ethyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate

Put 600 mg (1.08 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-[2-(diphenylmethylidene)hydrazino]pyridine-2-carboxylate, 378 mg (3.78 mmol) of 2,4-pentanedione, 186 mg (1.08 mmol) of paratoluenesulphonic acid and 5 mL of ethanol in a screw-top bottle. Heat the mixture at 120° C. while stirring for 48 h, then cool, and concentrate under reduced pressure. Then distribute the residue in 50 mL of EtOAc and 50 mL of a saturated aqueous solution of NaHCO₃. Dry the organic phase over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a heptane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 235 mg of ethyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate in the form of oil.

Yield=47%

18.3. 6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylic acid hydrochloride

According to the debenzylation/O-alkylation/saponification steps described in examples 4.6, 1.6 and 1.7 respectively, starting from 1 g (2.25 mmol) of ethyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylate, we obtain 460 mg of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylic acid hydrochloride.

Yield=43%

18.4. 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

According to the method described in example 9, peptide coupling effected between 460 mg (1 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-carboxylic acid hydrochloride and 156 mg (1.09 mmol) of 2-aminocyclohexane-2-carboxylic acid leads to 270 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(3,5-dimethyl-1H-pyrazol-1-yl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=46%

M.p. (° C.)=202

M C₂₃H₃₆ClN₃O₄=553; M+H=554

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.45 (s, 1H); 10.3 (s, 1H); 8.40 (s, 1H); 8.15 (s, 2H); 7.45 (d, 1H); 7.00 (m, 2H); 6.05 (s, 1H); 3.95 (t, 2H); 3.15 (m, 2H); 2.75 (d, 6H); 2.20 (s, 3H); 2.15 (m, 4H); 1.70 (s, 3H); 2.9-1.2 (m, 8H).

EXAMPLE NO. 19 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 80 19.1. 5-aminopyrazine-2-carbonitrile

Heat a suspension of 1.85 g (20.7 mmol) of copper cyanide and 1 g (20.7 mmol) of sodium cyanide in 20 ml of DMF to 135° C., while stirring. Add 3.6 g (20.7 mmol) of 5-bromopyrazin-2-amine to the solution obtained, and maintain the temperature of 135° C. for 18 h. Then add 2 equivalents of sodium cyanide and of copper cyanide and continue heating for a further 24 h. After cooling, add 100 mL of 0.3N aqueous solution of sodium cyanide, stir the mixture for 1 h at 40° C., then distribute it in 300 mL of EtOAc/water 1:1 mixture. After washing with 2×100 mL of water, dry the organic phase over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 100% of EtOAc. After concentration under reduced pressure, we obtain 1.24 g of 5-aminopyrazine-2-carbonitrile in the form of oil.

Yield=50%

19.2. Methyl 5-aminopyrazine-2-carboxylate

Reflux a solution of 2.24 g (18.65 mmol) of 5-aminopyrazine-2-carbonitrile and 9.45 mL (74.40 mmol) of boron trifluoride etherate in 50 mL of methanol for 2 h. Concentrate the reaction mixture under reduced pressure and take up the residue obtained in 200 mL of EtOAc and 10 mL of a saturated aqueous solution of NaHCO₃. Dry the organic phase over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc 1:1 mixture. After concentration under reduced pressure, we obtain 1.4 g of methyl 5-aminopyrazine-2-carboxylate in the form of oil.

Yield=49%

19.3. Methyl 5-amino-6-bromopyrazine-2-carboxylate

Add 1.79 g (10.05 mmol) of N-bromosuccinimide to a solution of 1.4 g (9.14 mmol) of methyl 5-aminopyrazine-2-carboxylate in 10 mL of acetonitrile. Stir the reaction mixture for 2 h at 20° C. then distribute in 100 mL of EtOAc/water 1:1 mixture. Wash the organic phase with 2×50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 50% of EtOAc. After concentration under reduced pressure, we obtain 1.66 g of methyl 5-amino-6-bromopyrazine-2-carboxylate in the form of yellow wax.

Yield=78%

19.4. Methyl 5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate

Stir a suspension of 137 mg (0.36 mmol) of (bis-benzonitrile)-palladium II dichloride and 183 mg (0.43 mmol) of diphenylphosphinobutane in 7 mL of toluene under argon for 30 min at room temperature. Then add, while bubbling with argon, 1.66 g (7.15 mmol) of methyl 5-amino-6-bromopyrazine-2-carboxylate, 1.97 g (7.51 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid, 2.4 mL of ethanol and 3.58 mL (7.15 mmol) of a 2N aqueous solution of sodium carbonate. Reflux the reaction mixture for 5 h 30 min and then distribute in 100 mL of a water/EtOAc 1:1 mixture. Wash the organic phase with 50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 50 to 100% of EtOAc. After concentration under reduced pressure, we obtain 1.33 g of methyl 5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate in the form of yellow wax.

Yield=50%

19.5. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylate

Add, dropwise, 0.82 mL (6.9 mmol) of tert-butyl nitrite to a solution of 1.28 g (3.46 mmol) of methyl 5-amino-6-[3-(benzyloxy)-4-chlorophenyl]pyrazine-2-carboxylate in 10 mL of anhydrous acetonitrile cooled to 0° C., under argon. After 2 h at 0° C., add 1.54 g of copper dibromide and stir the suspension obtained for 1 h 30 min at 65° C. After cooling, distribute the reaction mixture in 100 mL of EtOAc/water 1:1 mixture. Wash the organic phase with 3×50 mL of water and 50 mL of brine, then dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 645 mg of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylate in the form of yellow wax.

Yield=43%

19.6. Methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate

According to the method described in example 4.5, Suzuki coupling effected between 545 mg (1.26 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-bromopyrazine-2-carboxylate and 205 mg (1.51 mmol) of 2-methylphenylboronic acid leads to 430 mg of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate in the form of wax.

Yield=76%

19.7. 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

According to the debenzylation/O-alkylation/saponification/peptide coupling steps described in examples 4.6, 1.6, 1.7 and 9, starting from 485 mg (1.09 mmol) of methyl 6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate, we obtain 154 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=20%

M.p. (° C.)=162

M C₃₀H₃₅ClN₄O₄=550; M+H=551

¹H NMR (ppm, d6-DMSO, 400 MHz): 10.40 (s, 1H); 9.15 (s, 1H); 8.40 (s, 1H); 7.40 (d, 1H); 7.30 (m, 5H); 7.10 (dd, 1H); 3.85 (t, 2H); 3.15 (m, 2H); 2.75 (d, 6H); 1.95 (s, 3H); 2.3-1.3 (m, 12H).

EXAMPLE NO. 20 1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 129 20.1. Methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate

Put 5 g (22.5 mmol) of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate, 3.2 g (23.65 mmol) of 2-methylphenyl boronic acid in 45 mL of anhydrous toluene in a screw-top bottle. After dissolution, add 34 mL (67.6 mmol) of a 2N aqueous solution of sodium carbonate and degas the two-phase mixture for 30 min by bubbling with argon. Then add 1.3 g (1.13 mmol) of Pd(PPh₃)₄ and stir the reaction mixture vigorously at 110° C. for 48 h. After cooling, distribute the solution in 500 mL of EtOAc/brine 1:1 mixture and extract the aqueous phase again with 4×50 mL of EtOAc. Combine the organic phases, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 20% of EtOAc. After concentration under reduced pressure, we obtain 2 g of methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate in the form of yellow wax.

Yield 50%

20.2. Methyl 3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate

According to the method described previously (example 20.1), Suzuki coupling effected between 1.7 g (6.12 mmol) of methyl 3-amino-6-chloro-5-(2-methylphenyl)pyrazine-2-carboxylate and 3.2 g (12.24 mmol) of methyl 5-amino-6-bromopyrazine-2-carboxylate, 1.97 g (7.51 mmol) of [3-(benzyloxy)-4-chlorophenyl]boronic acid leads to 2.7 g of methyl 3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate in the form of gum.

Yield=80%

20.3. 1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

According to the debenzylation/O-alkylation/saponification/peptide coupling steps described in examples 4.6, 1.6, 1.7 and 9, starting from 263 mg (0.57 mmol) of methyl 3-amino-6-[3-(benzyloxy)-4-chlorophenyl]-5-(2-methylphenyl)pyrazine-2-carboxylate, we obtain 40 mg of 1-({[3-amino-6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-methylphenyl)pyrazin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=12.5%

M.p. (° C.)=138

M C₃₀H₃₆ClN₅O₄=565; M+H=566

¹H NMR (ppm, d6-DMSO, 400 MHz): 12.40 (s, 1H); 10.1 (s, 1H); 8.30 (s, 1H); 7.55 (s, 2H); 7.30 (q, 1H); 7.20 (m, 4H); 7.05 (s, 1H); 6.85 (d, 1H); 3.80 (t, 2H); 3.10 (m, 2H); 2.70 (s, 6H); 2.15 (d, 2H); 2.05 (m, 2H); 1.95 (s, 3H); 1.75 (t, 2H); 1.55 (m, 3H); 1.40 (m, 2H); 1.25 (m, 1H).

EXAMPLE NO. 21 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride Compound No. 105 21.1. 4-chloro-3-iodophenol

According to the steps of reduction/Sandmeyer reaction described in examples 12.4 and 12.1 respectively, starting from 25 g (144 mmol) of 4-chloro-3-nitrophenol we obtain 24 g of 4-chloro-3-iodophenol in the form of oil.

Yield=66%

21.2. 1-chloro-2-iodo-4-ethoxybenzene

Add 2 g (14.5 mmol) of K₂CO₃ and 1.16 mL (14.5 mmol) of iodoethane to a solution of 2.45 g (9.6 mmol) of 4-chloro-3-iodophenol in 30 mL of DMF. Heat the reaction mixture at 50° C. while stirring for 3 h, then distribute in 200 mL of ether/water 1:1 mixture. Wash the organic phase with 3×50 mL of water then dry over Na₂SO₄ and concentrate under reduced pressure. We obtain 2.38 g of 1-chloro-2-iodo-4-ethoxybenzene in the form of oil.

Yield=87%

21.3. (2-Chloro-5-ethoxyphenyl)boronic acid

Add, dropwise, 5.5 mL (8.8 mmol) of a 1.6N solution of butyllithium in hexane in the space of 30 min to a solution of 2.38 g (8.4 mmol) of 1-chloro-2-iodo-4-ethoxybenzene in 50 mL of anhydrous THF cooled under argon to −78° C. After 2 h at −70° C., add 1.74 g (9.2 mmol) of triisopropyl borate and stir the reaction mixture for 3 h at room temperature, then distribute in 200 mL of EtOAc/HCl aq 5N 1:1 mixture. Wash the organic phase with 50 mL of water, dry over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 10% of methanol. After concentration under reduced pressure, we obtain 990 mg of (2-chloro-5-ethoxyphenyl)boronic acid, in the form of oil.

Yield=59%

21.4. Methyl 5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate

According to the method described in example 4.5, the Suzuki reaction effected between 452 mg (2.26 mmol) of (2-chloro-5-ethoxyphenyl)boronic acid and 1 g (1.88 mmol) of methyl 6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate (obtained in 3 stages from 1-chloro-4-iodo-2-[(4-methoxybenzyl)oxy]benzene according to the borylation/Suzuki coupling/triflate steps described in examples 4.2, 4.3 and 4.4 respectively) leads to 700 mg of methyl 5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate in the form of oil.

Yield=70%

21.5. Methyl 5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylate

Add 1 mL (13 mmol) of trifluoroacetic acid to a solution of 700 mg (1.3 mmol) of methyl 5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate in 10 mL of DCM stirred at 0° C. Stir the reaction mixture for 2 h at 20° C. then concentrate under reduced pressure. Take up the residue in 50 mL of DCM and wash with 50 mL of a saturated aqueous solution of NaHCO₃. Dry the organic phase over Na₂SO₄ and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 524 mg of methyl 5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylate in the form of oil.

Yield=96%

21.6. 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

According to the O-alkylation/saponification/peptide coupling steps described in examples 1.6, 1.7 and 9, starting from 524 mg (1.25 mmol) of methyl 6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}-5-{[(trifluoromethyl)sulphonyl]oxy}pyridine-2-carboxylate, we obtain 125 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2-chloro-5-ethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Yield=18%

M.p. (° C.)=160

M C₃₂H₃₇Cl₂N₃O₅=613; M+H=614

¹H NMR (ppm, d6-DMSO, 400 MHz): 8.45 (s, 1H); 8.10 (d, 1H); 8.00 (d, 1H); 7.40 (d, 2H); 7.35 (s, 1H); 7.00 (m, 3H); 4.05 (m, 2H); 3.95 (m, 2H); 3.20 (m, 2H); 2.80 (s, 6H); 2.20 (d, 2H); 2.15 (m, 2H); 1.85 (t, 2H); 1.65 (m, 3H); 1.45 (m, 2H); 1.35 (m, 1H); 1.30 (t, 3H).

The chemical structures and physical properties of some examples of compounds according to the invention are shown in the following table.

Table of Compounds

TABLE I Some of the compounds presented below are in the form of hydrochloride. Melt- ing point No. A Z B p R₁ R₂ W X Y U (° C.)  1

(CH₂)₃ NMe₂ 0

Cl N CH H   175  2

(CH₂)₃ NMe₂ 0

Cl N CH H >200  3

(CH₂)₃ NMe₂ 0

Cl N CH H >200  4

(CH₂)₃ NMe₂ 0

Cl N CH H >200  5

(CH₂)₃ NMe₂ 0

H Cl N CH H   164  7

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl N CH H   202  8

(CH₂)₃ NMe₂ 1

H Cl N CH H   166  9

(CH₂)₃ NMe₂ 1

H Cl N CH H   170  10

(CH₂)₃ NMe₂ 0

H Cl N CH H >200  11

(CH₂)₃ NMe₂ 1

H Cl N CH H >200  12

(CH₂)₃ NMe₂ 0

Cl N CH H >200  13

(CH₂)₃ NMe₂ 0

CH₃ Cl N CH H >200  14

(CH₂)₃ NMe₂ 0 CH(Me)₂ CH₃ Cl N CH H >200  15

(CH₂)₀

0

Cl N CH H   215  16

(CH₂)₀

0

Cl N CH H   231  17

(CH₂)₃ NMe₂ 0

Cl N CH H   184  18

(CH₂)₃ NMe₂ 0

Cl N CH H   224  19

(CH₂)₀

0

Cl N CH H   217  20

(CH₂)₂ NMe₂ 0

Cl N CH H   219  21

(CH₂)₃ NMe₂ 0

Cl N CH H   192  22

(CH₂)₃ NMe₂ 0

Cl N CH H   214  23

(CH₂)₃ NMe₂ 0

Cl N CH H   199  24

(CH₂)₃ NEt₂ 0

Cl N CH H   189  25

(CH₂)₃ NMe₂ 0

Cl N CH H   197  26

(CH₂)₃ NMe₂ 0

Cl N CH H   219  27

(CH₂)₃ NMe₂ 0

Cl N CH H   209  28

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl CH CH H   152  29

(CH₂)₃ NMe₂ 1 CH(Me)₂ H Cl CH N H   139  30

(CH₂)₃ NMe₂ 0

H Cl N CH H   160  31

(CH₂)₂

0

Cl N CH H   175  32

(CH₂)₂

0

Cl N CH H   160  33

(CH₂)₃ NMe₂ 1

Cl N CH H 168-   170  34

(CH₂)₃ NMe₂ 0

Cl N CH H 146-   150  35

(CH₂)₃ NMe₂ 0

Cl N CH H >200  36

(CH₂)₃ NMe₂ 0

Cl N CH H   188  37

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl H CH H   145  38

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl H CH H   162  39

(CH₂)₃ NMe₂ 0

Cl N CH H 195-   198  40

(CH₂)₃ NMe₂ 0

Cl N CH H 178-   184  41

(CH₂)₃ NMe₂ 0

Cl N CH H   222  42

(CH₂)₃ NMe₂ 0

Cl N CH H 220-   222  43

(CH₂)₃ NMe₂ 0

CF₃ N CH H 230-   232  44

(CH₂)₃

0

Cl N CH H 208-   210  45

(CH₂)₃

0

Cl N CH H >200  46

(CH₂)₃

0

Cl N CH H >200  47

(CH₂)₂

0

Cl N CH H   185  48

(CH₂)₂

0

Cl N CH H   156  49

(CH₂)₂CHMe NMe₂ 0

Cl N CH H   196  50

CH(Me)(CH₂)₂ NMe₂ 0

Cl N CH H   188  51

(CH₂)₃ NMe₂ 0

Cl N CH H   216  52

(CH₂)₃ NMe₂ 0

Cl N CH H 188-   189  53

CH₂CH(OH)CH₂ enantiomer (S) NMe₂ 0

Cl N CH H   200  54

(CH₂)₂ NEt₂ 0

Cl N CH H   178  55

(CH₂)₃ NMe₂ 0

Cl N CH H   140  56

(CH₂)₃ NMe₂ 0

Cl N CH H >200  57

(CH₂)₃ NMe₂ 0

Cl N CH H 190-   200  58

(CH₂)₃ NMe₂ 0

Cl N CH H   174  59

(CH₂)₃ NMe₂ 0 CH(Me)₂ enantiomer (R) H Cl N CH H   138  60

(CH₂)₃ NMe₂ 0

Cl N CH H   196  61

(CH₂)₃ NMe₂ 0

Cl N CH H   172  62

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (R) H Cl N CH H   145  63

CH₂CH(OH)CH₂ enantiomer (R) NMe₂ 0

Cl N CH H   200  64

(CH₂)₃ NMe₂ 0

Cl N CH H   174  65

(CH₂)₃ NMe₂ 0

Cl N CH H   165  66

(CH₂)₃ NMe₂ 0

Cl N CH H   158  67

(CH₂)₃ NMe₂ 0

Cl N CH H   150  68

(CH₂)₃ NMe₂ 0

Cl N CH H   237  69

(CH₂)₃ NMeEt 0

Cl N CH H   156  70

(CH₂)₃ NMe₂ 0

Cl N CH H   144  71

(CH₂)₃ NMe₂ 0

Cl N CH H   196  72

(CH₂)₃ NMe₂ 1 CH(Me)₂ enantiomer (S) H Cl N CH H   157  73

(CH₂)₃ NMe₂ 0

Cl N CH H   172  74

(CH₂)₃ NMe₂ 0

Cl N CH H   230  75

(CH₂)₃ NMe₂ 0

Cl N CH H   202  76

(CH₂)₃ NMe₂ 0

Cl N CH H   160  77

(CH₂)₃ NMe₂ 0

CH₂CH₃ N CH H   200  78

(CH₂)₃ NMe₂ 0

Cl N CH H   158  79

(CH₂)₃ NMe₂ 0

Cl N CH H   164  80

(CH₂)₃ NMe₂ 0

Cl N N H   162  81

(CH₂)₃ NMe₂ 1

H Cl N CH H   136  82

(CH₂)₃ NMe₂ 1

H Cl N CH H   140  83

(CH₂)₃ NMe₂ 0

Cl N CH H   175  84

(CH₂)₃ NMe₂ 0

Cl N CH H   169  85

(CH₂)₃ NMe₂ 0

Cl N CH H   146  86

(CH₂)₃ NMe₂ 0

Cl N CH H   163  87

(CH₂)₃ NMe₂ 0

Cl N CH H   117  88

(CH₂)₃ NMe₂ 0

Cl N CH H   148  89

(CH₂)₃ NMe₂ 0

Cl N CH H   186  90

(CH₂)₃ NMe₂ 0

Cl N CH H   152  91

(CH₂)₃ NMe₂ 1 C(Me)₃ H Cl N CH H   165  92

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N CH H   170  93

(CH₂)₃ NMe₂ 0

Cl N CH H   134  94

(CH₂)₃ NMe₂ 0

Cl N CH H   144  95

(CH₂)₃ NMe₂ 0

Cl N CH H   168  96

(CH₂)₃ NMe₂ 0

Cl N CH H   147  97

(CH₂)₃ NMe₂ 0

Cl N CH H   154  98

(CH₂)₃ NMe₂ 0

Cl N CH H   149  99

(CH₂)₃ NMe(CH₂)₂OH 0

Cl N CH H   140 100

(CH₂)₃ NMe₂ 0

Cl N CH H   196 101

(CH₂)₃ NMe₂ 0

Cl N CH H   157 102

(CH₂)₃ NMe₂ 0

Cl N CH H   195 103

(CH₂)₃ NMe₂ 0

Cl N CH H   147 104

(CH₂)₃ NMe₂ 0

Cl N CH H   152 105

(CH₂)₃ NMe₂ 0

Cl N CH H   160 106

(CH₂)₃ NMe₂ 0

Cl N CH H   287 107

(CH₂)₃ NMe₂ 0

Cl N CH H   138 108

(CH₂)₃ NMe₂ 0

Cl N CH H   152 109

(CH₂)₃ NMe₂ 0

Cl N CH H   147 110

(CH₂)₃ NMe₂ 0

Cl N CH H   176 111

(CH₂)₃ NMe₂ 0

Cl N CH H   185 112

(CH₂)₃ NMe₂ 0

Cl N CH H   158 113

(CH₂)₃ NMe₂ 0

Cl N CH H   172 114

(CH₂)₃ NMe₂ 0

Cl N CH H   157 115

(CH₂)₃ NMe₂ 0

Cl N CH H   142 116

(CH₂)₃ NMe₂ 0

Cl N CHOMe H   205 117

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N CH H   130 118

(CH₂)₃ NMe₂ 0

Cl N CH H   173 119

(CH₂)₃ NMe₂ 0

Cl N CH H   162 120

(CH₂)₃ NMe₂ 0

Cl N CH H   152 121

(CH₂)₃ NMe₂ 0

Cl N CH H   144 122

(CH₂)₃ NMe₂ 0

Cl N CH H   134 123

(CH₂)₃ NMe₂ 0

Cl N N H   135 124

(CH₂)₃ NMe₂ 0

Cl N CH H   140 125

(CH₂)₃ NMe₂ 0

Cl N CH H   148 126

(CH₂)₃ NMe₂ 0

Cl N N H   122 127

(CH₂)₃ NMe₂ 1 C(Me)₃ enantiomer (S) H Cl N N H   141 128

(CH₂)₃ NMe₂ 0

Cl N CH H   115 129

(CH₂)₃ NMe₂ 0

Cl N N NH₂   138 130

(CH₂)₃ NMe₂ 0

Cl N N NH₂   158 131

(CH₂)₃ NMe₂ 0

Cl N CH H   144 132

(CH₂)₃ NMe₂ 0

Cl N CH H   160 133

CH₂(CHF)CH₂ NMe₂ 0

Cl N CH H   158 134

(CH₂)₃ NMe₂ 0

Cl N CH H   155 135

(CH₂)₃ NMe₂ 0

Cl N CH H   274 136

(CH₂)₃ NMe₂ 0

Cl N CH NHMe   155

Table of Compounds

R₈ represents

TABLE II No. A Z B R₈ Melting point (° C.) 137

(CH₂)₃ NMe₂

170 138

(CH₂)₃ NMe₂

166 139

(CH₂)₃ NMe₂

180-190 140

(CH₂)₃ NMe₂

190-200 141

(CH₂)₃ NMe₂

160 142

(CH₂)₃ NMe₂

>250  143

(CH₂)₃ NMe₂

>250  144

(CH₂)₂

150 145

(CH₂)₃ NMeEt

160 146

(CH₂)₄ NMe₂

148 147

(CH₂)₃ NEt₂

158 148

(CH₂)₃ NMe₂

162 149

(CH₂)₃ NMe₂

170 150

(CH₂)₃ NMe₂

167-170 151

(CH₂)₃ NMe₂

202 152

(CH₂)₃ NMeEt

178 153

(CH₂)₃ NEt₂

162 154

(CH₂)₃ NMe₂

174 155

(CH₂)₃ NMe₂

170-175 156

(CH₂)₃ NMePr

138 157

(CH₂)₃ NMeEt

145 158

(CH₂)₃ NMe₂

150 159

(CH₂)₃ NMe₂

165 160

CH₂CH(Me)CH₂ NMe₂

158

The compounds according to the invention have undergone pharmacological testing for determining the properties of the compounds of the invention, including in particular:

-   -   a test in vitro of intracellular calcium mobilization (FlipR         test) employing urotensin II antagonists (the compounds of the         present invention) of the human GPR14 receptor,     -   a function test of contraction of rat aorta rings, also         employing urotensin II antagonists represented by the compounds         of the present invention.

These two tests are described below:

1. FlipR (Fluorometric Imaging Plate Reader) Protocol

1.1 Purpose

The purpose is to measure the activation of the GPR14 receptor by human urotensin II.

1.2. Test Principle

GPR14 is a Gq-coupled receptor with 7 transmembrane domains. Its activation by a specific ligand causes an increase in Ca²⁺ in the cell via the PLC (Phospholipase C), IP3 (Inositol-1,4,5-triphosphate) DAG (Diacylglycerol) pathway. The increase in Ca²⁺ in the cell is measured by means of the Fluo4AM permeating probe (mono-excitation, mono-emission probe) which binds to free Ca²⁺ and emits at 520 nm. The free probe is non-fluorescent in the absence of Ca²⁺.

1.3. Protocol

Experimental Plan

1) Seeding of the cells on D−1 (Day−1) or D−2

2) Incorporation/loading (D0) of the probe (1 h)

3) Addition of the products to the FlipR and measurement

4) Addition of the ligand to the FlipR and measurement in the presence of the products

5) Processing and exporting the data

CHOGPR14 Cells

The cells are cultivated in complete medium in Flask T225. For the experiments, the cells are transplanted in 200 μl of culture medium in 96-well (black, transparent-bottom) plates at a rate of 60 000 cells/well for use on D+1 or 40 000 cells/well for use on D+2.

Incorporation of the Fluo 4 M

The Fluo-4AM is prepared at 20 mM then aliquots are taken (50 μl) and stored at −20° C. away from the light. A solution of pluronic acid at 200 mg/ml in DMSO is also prepared (it has a shelf life of one week at room temperature away from the light).

The cells are charged with the Fluo-4AM+pluronic acid mixture (aliquot 50 μl+50 μl of pluronic acid) diluted to 1/100 in the measurement buffer.

After washing the wells with 150 μl of measurement buffer (cf. annex), the cells are then charged as follows:

-   -   distribution of 100 μl of measurement buffer in each well     -   addition of 10 μl of the Fluo-4AM+pluronic acid mixture diluted         to 1/100.

The cells are incubated for 1 h at 37° C. away from the light, in an incubator in the presence of 5% CO₂.

The cells are then washed 3 times with 150 μl of measurement buffer to remove the excess of the probe. A volume of 150 μl of buffer is added to each well at the end of washing.

After incubating the plates for 20 min at room temperature away from the light, they are placed in the FlipR for measurement of fluorescence.

The level of basic incorporation of the Fluo-4 is checked for each plate (sd<10%) before the first injection.

After stabilization of the basic signal, the GPR14 inhibiting compounds are injected by the FlipR under a volume of 50 μl from a dilution plate effected with Biomek 2000 in measurement buffer. Urotensin II (3 nM final, concentration equal to the EC₅₀) is added under a volume of 50 μl by the FlipR on the cells from a stock plate at 15 nM diluted in the measurement buffer. Data recording is carried out continuously throughout the experiment.

1.4. Data Analysis

For each plate, the basic fluorescence before injection of the compounds is standardized by the “spatial uniformity correction” function of the FlipR. The values of fluorescence measured just before injection of urotensin II (min) and those of the fluorescence measured at the peak of the effect of urotensin II (max) are exported under Excel. In each plate, a series of wells is treated with urotensin alone in the absence of inhibitor compound. The min and max fluorescence values for these wells are averaged for defining 100% effect of urotensin II. The percentage inhibition calculated for each concentration of inhibitor is calculated as follows:

-   -   for each well with Uro II (urotensin II)+inhibitor, calculation         of the delta product value=max−min     -   for the well with Uro II alone, calculation of the value delta         Uro II (average max−average min)

The percentage inhibition for each concentration of product is calculated as follows: Inhibition (%)=100×(delta Uro II−delta product)/delta Uro II 1.5. Annex Composition of the Measurement Buffer (in Demineralized Water, to be Prepared when Required)

Qsf 500 mL QSF 1 L QSF 2 L HBSS 50 mL 100 mL 200 mL MgSO₄ 19.72 g/L 5 mL 10 mL 20 mL Hepes 2.38 g 4.76 g 9.52 g Na₂CO₃ 35 g/L 5 mL 10 mL 20 mL CaCl₂ 14.7 g/L 5 mL 10 mL 20 mL BSA 10% 50 mL 100 mL 200 mL HBSS = Hanks' Balanced Salt Solution BSA = Bovine Serum Albumin

The various saline solutions can be stored for 2 months at 4° C.

Adjust the volume of H₂O and add probenecid dissolved in 1N sodium hydroxide

+Probenecid 0.355 g in 5 mL 0.71 g in 10 mL of 1.42 g in 20 mL of 1N NaOH 1N NaOH of 1N NaOH

Check for pH 7.4.

1.6. Equipment and Materials

Human urotensin II (Bachem H-4768)

Fluo-4AM (Molecular Probes (F14202 5×1 mg)

Probenecid (Sigma P8761 100 g)

Pluronic acid (Molecular Probes P6867)

HBSS 10× (Gibco 14185-045)

HEPES (acid) (Sigma H3375)

Sodium carbonate (Sigma S7795) Na₂CO₃

Magnesium sulphate (Sigma M7774) MgSO₄

Calcium chloride (Sigma C5080) CaCl₂

Black tips (Molecular Devices 9000-0549)

Black plates, 96-well (Beckton Dickinson 356640)

DMSO (Sigma D 5879)

1.7. Results

The compounds tested have an IC50 in the FlipR test below 10000 nM. Some of these compounds have an IC50 in the FlipR test below 100 nM. For example, compounds No. 18, 34, 37, 58, 61, 65, 66, 67, 70, 71, 75, 79, 120, 123, 129 in the table have IC50 of 19, 25, 72, 28, 9, 32, 4.2, 13, 32, 24, 21, 31, 16, 4.2 and 15 nM, respectively.

2. Contraction of Rat Aorta

2.1. Protocol

Male Sprague-Dawley rats (400-500 g; C. River, France) are anaesthetized with 6% sodium pentobarbital (Ceva SantéAnimale) by intraperitoneal injection (0.4-0.5 ml), and then euthanized by exsanguination. The aortas are removed, washed and, after removing the endothelium, are cut into 4 rings of about 0.2-0.3 cm. Each fragment is placed in a container for isolated organs, containing 20 mL of Krebs solution with the following composition (mM): NaCl 118; KCl 4.7; MgCl₂ 1.2; CaCl₂ 2.6; NaHCO₃ 25; glucose 11.1; (pH=7.4).

The tissue, maintained at 37° and aerated with a stream of carbogen (95% O₂-5% CO₂), is connected to a Grass FT03 isometric sensor under a basic strain of 2 g, and to a Gould series 6600 amplifier for recording the variations in strain. Data acquisition is effected automatically on an HP Compaq PC using IOX software (version 2.2) from the company Emka.

After stabilization for 60 min, the viability of the preparation is tested by prestimulation with 60 mM of KCl. This contraction is repeated a second time and the strain that developed will serve as reference (100%) for standardizing the response to urotensin II.

The curve of concentration v. contractile response to urotensin II is then constructed cumulatively until a maximum response is obtained.

A single concentration-response curve is recorded owing to the desensitization effects induced by urotensin II.

The antagonists or the vehicle (DMSO 0.15% maximum) are added to the container 30 min before the agonist.

2.2. Compound

Human urotensin II is obtained from Bachem Ltd (UK) and is dissolved in 0.1% of BSA.

2.3. Data Analysis

The responses are expressed as percentage of the maximum contraction observed with KCl. The results represent the mean+/−sem of the individual responses. N corresponds to the number of animals per batch.

Analysis of the sigmoid curves using the Everstat software (De Lean A, Munson P J, Rodbard D., Am J Physiol 1978; 235(2): E97-102.) permitted the EC₅₀ (concentration producing 50% of the maximum response) and the E_(max) (maximum effect) to be determined.

To evaluate the potency of the antagonists based on a single concentration, the pKb were calculated according to the equation: pKb=−log [antagonist]M+log(concentration-ratio−1) (Furchgott R F, Blaschko H, Muscholl E, editors. Handbook of Exp Pharmacol, Catecholamines, Springer, Berlin Heidelberg N.Y.; 1972; 33:283-335) where concentration-ratio is the EC₅₀ of the agonist in the presence of the antagonist divided by the EC₅₀ of the agonist in the absence of the antagonist.

If several concentrations of antagonist are tested, the pA₂ (±confidence limits) is calculated by the Schild plot method (Arunlakshana O and Schild H O, Br J Pharmacol, 1959; 14:48-58).

2.4. Results

The compounds tested have a pKb between 5.5 and 8.15. As examples, compounds No. 18, 34, 37, 58, 61, 65, 66, 67, 70, 71, 75, 79, 120, 123, 129 in the table have a pKb of 6.5; 7.1; 7.5; 6.6; 7.1; 6.5; 6.7; 6.7; 6.2; 6.3; 6.6; 6.8; 7.1; 6.5; 6.8 respectively.

The compounds according to the invention can therefore be used for the preparation of medicinal products, in particular of medicinal products that are inhibitors of the urotensin II receptors.

Thus, according to another of its aspects, the invention relates to medicinal products that comprise a compound of formula (I), or a salt of addition of the latter to a pharmaceutically acceptable acid of the compound of formula (I).

These medicinal products find application in therapeutics, notably in the treatment and/or prevention of congestive heart failure, ischaemic heart disease, myocardial infarction, cardiac hypertrophy and fibrosis, coronary diseases and atherosclerosis, systemic arterial hypertension, pulmonary hypertension, portal hypertension, post-angioplasty restenosis, renal failure and more particularly acute and chronic renal failure of diabetic and/or hypertensive origin, diabetes, inflammation in general, fibrosis in general and aneurysms.

These medicinal products also find application in therapeutics, in the treatment and/or prevention of disorders of the central nervous system, including notably neurodegenerative diseases, cerebrovascular accidents, stress, anxiety, aggressiveness, depression, schizophrenia, or sleep disorders.

Medicinal products comprising compounds that are antagonists of urotensin II such as the compounds according to the invention also find application in therapeutics, in the treatment and/or prevention of vomiting.

These medicinal products also find application in therapeutics in the treatment of some cancers. These medicinal products also find application in therapeutics, in the treatment and/or prevention of asthma and respiratory diseases.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.

Said excipients are selected according to the pharmaceutical form and the desired method of administration, from the usual excipients that are known by a person skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, or its salt, can be administered in unit dosage form, mixed with conventional pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the aforementioned disorders or diseases.

The appropriate unit dosage forms comprise the forms for administration by the oral route, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular, intranasal administration, administration by inhalation, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms for rectal administration, and implants. For topical application, compounds according to the invention can be used in creams, gels, ointments or lotions.

As an example, a unit dosage form of a compound according to the invention in the form of a tablet can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg  Croscarmellose sodium  6.0 mg Maize starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate  3.0 mg

According to another of its aspects, the present invention also relates to a method of treatment of the above-mentioned pathologies that comprises the administration, to a patient, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts.

As used herein, the following definitions apply:

“Patient” means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

“Therapeutically effective amount” means a quantity of the compound which is effective in treating the named disorder or condition.

“Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.

The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.

The present invention is not to be limited in scope by the specific embodiments describe herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Various publications are cited herein, the disclosures of which are incorporated by reference in their entireties. 

The invention claimed is:
 1. A compound of formula (IV):

in which: X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen or halogen atom or an alkyl or alkoxy group; U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group; A represents an aryl, heteroaryl or heterocycloalkyl group, wherein said aryl group is a monocyclic aromatic group comprising 5 or 6 carbon atoms; said heteroaryl group is a cyclic aromatic group comprising 5 or 6 atoms, one or more of which are heteroatoms; and said heterocycloalkyl group is a saturated cyclic group that has 3 to 8 carbon atoms, in which one or two carbons are substituted with a nitrogen atom, wherein said aryl, heteroaryl or heterocycloalkyl group is optionally substituted in any positions with one or more groups selected from halogen atom, cyano, alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl, —SO— and —SO₂-alkyl groups, wherein R and R′ represent, independently of one another, a hydrogen atom or an alkyl group, and p is an integer between 1 and 5; W represents a halogen atom, an alkyl group or a haloalkyl group; Z represents a bond, a cycloalkylene group or an alkylene group optionally substituted with one or more groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups; B represents: either a group —NR4R5, where R4 and R5 represent, independently of one another, an alkyl, cycloalkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionally substituted with an alkyl group, or B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group; or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, in which X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen or halogen atom or an alkyl or alkoxy group; or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
 3. The compound of claim 1, in which U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group; or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
 4. The compound of claim 1, in which A is selected from phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl and pyrrolidinone groups, any of which is optionally substituted.
 5. The compound of claim 1, in which W represents a halogen atom, an alkyl group or a haloalkyl group; or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
 6. The compound of claim 1, in which Z represents a bond, a cycloalkylene group or an alkylene group optionally substituted with one or more groups selected from a halogen atom and the alkyl, hydroxy and alkoxy groups; or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof.
 7. The compound of claim 1, in which B represents a group —NR4R5, where R4 and R5 represent, independently of one another, an alkyl, cycloalkyl, hydroxyalkyl or fluoroalkyl group, or alternatively R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring, optionally substituted with an alkyl group, or an enantiomer, diastereomer, racemate, hydrate, solvate or pharmaceutically acceptable salt thereof.
 8. The compound of claim 1, in which B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group; or an enantiomer, diastereomer, racemate, hydrate, solvate or pharmaceutically acceptable salt thereof.
 9. The compound of claim 1, in which: X and Y represent, independently of one another, a nitrogen atom or a —CR3- group, where R3 represents a hydrogen atom or an alkoxy group; U represents a hydrogen atom or a group NHR7, where R7 is a hydrogen atom or an alkyl group; A represents an aryl, heteroaryl or heterocycloalkyl group selected from phenyl, benzodioxolyl, thienyl, thiazolyl, pyridinyl, pyrazolyl and pyrrolidinone groups, wherein said aryl or heteroaryl group is optionally substituted in any positions with one or more groups selected from halogen atom, cyano, alkyl, haloalkyl, hydroxy, alkoxy, —O—(CH₂)_(p)—O-alkyl, haloalkoxy, —NRR′, —NR—CO-alkyl and —SO₂-alkyl groups, wherein R and R′ represent, independently of one another, a hydrogen atom or an alkyl group and p is an integer between 1 and 5; W represents a halogen atom, an alkyl group, or a haloalkyl group; Z represents a bond or an alkylene group optionally substituted with at least one group selected from halogen atom, alkyl, and hydroxy groups; B represents: either a group —NR4R5, wherein R4 and R5 represent, independently of one another, an alkyl, hydroxyalkyl group, or alternatively, R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, such as a pyrrolidinyl or piperidinyl ring, or B represents a heterocycle of the following formula:

where m and n represent, independently of one another, 0, 1 or 2, and where R6 and R7 represent, independently of one another, a hydrogen atom or an alkyl or cycloalkyl group.
 10. The compound of claim 1, in which: X and Y represent, independently of one another, a nitrogen atom or a CH group; A represents a phenyl, pyridinyl, or pyrrolidinone group, substituted in any positions with 1 to 2 groups selected from halogen atom, alkyl, trifluoromethyl, methoxy, and N,N-dimethylamine groups; U represents a hydrogen atom or a group NHR7, wherein R7 is a hydrogen atom; W represents a chlorine atom or a trifluoromethyl group; Z represents a bond or an alkylene group optionally substituted with a methyl group; B represents: either a group —NR4R5, wherein R4 and R5 represent, independently of one another, an alkyl group, or alternatively, R4 and R5 form, with the nitrogen atom to which they are attached, a 5- or 6-membered ring, or B represents a heterocycle selected from the following formulas:

where m=1 or 2, and R6 represents an ethyl or methyl group.
 11. The compound of claim 1, in which: X represents a nitrogen atom and Y represents a CH group; A represents a phenyl or pyridinyl group, substituted in positions 2, 4, 5 and 6 by one or two groups selected from halogen atom, alkyl groups, trifluoromethyl, methoxy, and N,N-dimethylamine; U represents a hydrogen atom or a group NHR7, wherein R7 is a hydrogen atom; W represents a chlorine atom or a trifluoromethyl group; Z represents a bond, or an ethylene, propylene, or methylpropylene group; B represents: either a group —NR4R5, wherein R4 and R5 represent, independently of one another, a methyl, ethyl, or propyl group, or form together with the nitrogen atom to which they are attached a 5- or 6-membered ring, or B represents a heterocycle of the following formula:


12. A compound of claim 1, comprising a hydrochloride salt form of said compound. 